CN101490058A

CN101490058A - Antiviral agents

Info

Publication number: CN101490058A
Application number: CNA2007800266569A
Authority: CN
Inventors: 弗朗兹·乌尔里希·施米茨; 克里斯托弗·唐·罗伯茨; 罗纳德·康拉德·格里菲斯; 亚诺什·博詹斯基; 松·明·范
Original assignee: Genelabs Technologies Inc
Current assignee: Genelabs Technologies Inc
Priority date: 2006-07-14
Filing date: 2007-07-12
Publication date: 2009-07-22
Also published as: EP2044083A1; TW200813070A; RU2009105196A; AR062258A1; WO2008008907A2; PE20080427A1; MX2009000513A; WO2008008907A3; AU2007272441A1; AU2007272441A2; BRPI0714346A2; CA2657651A1; WO2008008912A1; KR20090033881A; JP2009543807A

Abstract

Disclosed are compounds and compositions of Formula (I) and their uses for treating Flaviviridae family virus infections.

Description

Antiviral agent

The cross reference of related application

The right of priority that No. the 60/831st, 040, the co-pending U.S. Provisional Application case of the application's case opinion application on July 14th, 2006, its mode of quoting is in full incorporated this paper into.

Technical field

The present invention relates to the medical chemistry field, relate in particular to be used for the treatment of mammiferous to compound, composition and the method for small part by the virus infection that flaviviridae mediated.

Reference

Quote the following discloses case with the subscript digital form in the application's case:

1. (Szabo E.) waits people, pathology oncology studies (Pathol.Oncol.Res.) 2003,9:215-221 to this bundle uncle .E..

2. Hough Na Geer J.H. (Hoofnagle J.H.), hepatology (Hepatology) 1997,26:15S-20S.

3. hold in the palm gloomy B.J. of horse (Thomson B.J.) and fragrant strange R.G. (Finch R.G.), Clinical microorganism infects (ClinMicrobial Infect.) 2005,11:86-94.

4. gloomy western K. (Moriishi K.) and loose Pu Y. (Matsuura Y.), antiviral chemotherapy (Antivir.Chem.Chemother.) 2003,14:285-297.

5. (Fried M.W.) waits people, New England Journal of Medicine (N.Engl.J Med) 2002,347:975-982 to Fred M.W..

6. (Ni is Z.J.) with the graceful A.S. of waag (Wagman, the A.S.) current view (Curr.Opin.Drug Discov.Devel.) 2004,7 in drug discovery and the exploitation, 446-459 for Buddhist nun Z.J..

7. (Beaulieu is P.L.) with ginseng Qu Zuosi Y.S. (Tsantrizos, the Y.S.) current view in the drug research (Curr.Opin.Investig.Drugs) 2004,5,838-850 than excellent Shandong P.L..

8. (Griffith R.C.) waits people, medical chemistry annual report (Ann.Rep.Med.Chem) 39,223-237,2004 to Greaves R.C..

9. (Watashi K.) waits people, molecular cell (Molecular Cell), 19,111-122,2005 to cross rapids K..

10. (Horsmans Y.) waits people, hepatology (Hepatology), 42,724-731,2005 to Huo Simansi Y..

Background technology

Chronic HCV infection is the main health problem relevant with liver cirrhosis, hepatocellular carcinoma and liver failure.According to estimates, the whole world has 100,017,000 chronic carrier to be in the risk of development hepatopathy. ^1,2Only, just have 2,700,000 people to be subjected to the HCV chronic infection, and in 2000, relevant with HCV according to estimates death toll expected that this numeral will significantly increase year by year between 8,000 and 10,000 in the U.S..HCV infects and hides in most of chronic infection (and infectivity) carrier body, and these carrier may can not experience clinical symptom in many years.Liver cirrhosis finally can cause liver failure.Now generally acknowledge it is the leading reason of carrying out liver transplantation by the caused liver failure of chronic HCV infection.

HCV is the member of flavivirus (Flavivirdae) section of infecting the RNA viruses of animal and human's class.Genome is the single stranded RNA with about 9.6 kilobase, and by one 5 ' end and 3 ' distolateral connect untranslated district (5 '-open reading frame that the coding of UTR and 3 '-UTR) has about 3000 amino acid whose polymeric protein forms.Described polymeric protein is served as at least 10 kinds for the precursor that duplicates and assemble the vital indivedual virus proteins of progeny virus particle.Being constructed as follows of structural protein and nonstructural proteins in the HCV polymeric protein: C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b.Because the replicative cycle of HCV does not relate to any DNA intermediate and virus is not incorporated in the host genome, so HCV infects and can cure in theory.Although the pathology that HCV infects mainly influences liver, also find this viroid in other cell type (comprising peripheral blood lymphocyte) in vivo. ^3，4

At present, be interferon alpha (IFN-α) and the combined therapy of virazole (ribavirin) for the standard treatments of chronic hcv, and this need treatment phase of at least six (6) individual months.IFN-α belongs to the naturally occurring small protein matter family that has such as characteristic biological actions such as antiviral, immunomodulatory and anti-tumor activities, and described naturally occurring small protein matter is to some diseases, especially virus infection reacts and produces and secrete by most of animal karyocyte.Important growth and the differentiation conditioning agent of IFN-α for influencing cell communication and immune control.With interferon therapy HCV usually with adverse side effect, such as tired, heating, shiver with cold, headache, myalgia, arthrodynia, slight alopecia, psychosis effect and associated conditions, autoimmunity phenomenon and associated conditions and abnormal thyroid function.Virazole (a kind of inosine 5 '-single phosphate dehydrogenase (IMPDH) inhibitor) effect of enhancing IFN-α aspect treatment HCV.Although the introducing virazole, the patient above 50% does not eradicate virus because of the current standard treatment of interferon-' alpha ' (IFN) and virazole yet.So far, make the standard treatment of chronic hepatitis c into combination that polyoxyethylene glycol IFN-α adds virazole.Yet many patients still have apparent side effect, and this side effect is main relevant with virazole.Virazole causes significant hemolytic action at 10-20% in patient's body of current recommended dose treatment, described medicine also has teratogenecity and embryotoxicity simultaneously.Even, still have quite a few patient not produce the reaction that virus load continues reduction along with recent improvement ⁵, and obviously need be used for the more effective antiviral therapy that HCV infects.

The current several different methods of just seeking is to resist virus.It for example comprises that application antisense oligonucleotide or ribozyme suppress HCV and duplicate.In addition, directly suppress the low-molecular weight compound that HCV protein and viral interference duplicate and be regarded as the strategy that noticeable control HCV infects.In viral target spot, NS3/4a proteolytic enzyme/helicase and NS5b RNA RNA-dependent polysaccharase are regarded as the viral target spot of the tool prospect of new drug. ^6-8

Except that target virogene and its transcribe with translation product, also can obtain antiviral activity by the necessary host cell proteins matter of target virus replication.For instance, cross rapids people such as (Watashi) and show how to obtain antiviral activity by suppressing host cell cyclophilin (cyclophilin). ⁹Perhaps, proved that also effective TLR7 agonist can reduce human intravital HCV plasma content. ¹⁰

Yet above-claimed cpd does not all make progress in clinical trial. ^6，8

The popularity degree in worldwide in view of HCV and other member of flaviviridae, and also select in view of limited treatment, press for the novel active drug that is used for the treatment of by these viral caused infection.

Summary of the invention

The present invention relates to be used for the treatment of compounds, composition and the method for the mammiferous virus infection that is mediated by flaviviridae member (such as HCV) to small part.Specifically, compound of the present invention is represented by formula (I) or its pharmaceutically acceptable salt, ester, steric isomer, prodrug or tautomer:

Wherein:

Y is selected from by aryl, heteroaryl, is substituted aryl and is substituted the group that heteroaryl is formed;

HET is selected from the group that is made up of following: 6 yuan of arylidene rings; Contain 1,2 or 3 heteroatomic 6 yuan of inferior heteroaryl ring that are selected from N, O or S; With the dicyclo with following formula:

Or

Wherein HET is randomly through (X) _tReplace, X is selected from by alkyl, is substituted alkyl, alkoxyl group, is substituted alkoxyl group, amino, be substituted the group that amino, halogen, hydroxyl and nitro are formed; T equals 0,1 or 2 integer; W ¹, W ⁴And W ⁵Be N or CH independently; W ³Be N, CH or key, condition is to be no more than a nitrogen in the described dicyclo randomly to form the N-oxide compound through oxidation; And each dotted line is represented two singly-bound or two keys between the adjacent atom independently, and condition is when being singly-bound for one in the dotted line, and described adjacent atom is respectively hung oneself 1 or 2 hydrogen atom replacement to satisfy its valence state;

Among D or the E one is C-R ^aAnd another person among D or the E is S;

R ^aBe independently selected from by hydrogen, alkyl with R and be substituted the group that alkyl is formed;

Q is selected from by cycloalkyl, is substituted cycloalkyl, cycloalkenyl group, is substituted cycloalkenyl group, heterocyclic radical, be substituted heterocyclic radical, aryl, be substituted aryl, heteroaryl and be substituted the group that heteroaryl is formed; And

Z is selected from the group that is made up of following:

(a) carboxyl and carboxyl ester;

(b)-C (X ⁴) NR ⁸R ⁹, X wherein ⁴For=O ,=NH or=the N-alkyl, R ⁸And R ⁹Be independently selected from by hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted the group that heterocyclic radical is formed; Perhaps R ⁸And R ⁹Nitrogen-atoms together with its side joint forms heterocycle, is substituted heterocycle, heteroaryl ring or be substituted the heteroaryl ring group;

(c)-C (X ³) NR ²¹S (O) ₂R ⁴, X wherein ³Be selected from=O ,=NR ²⁴With=S, wherein R ²⁴For hydrogen, alkyl or be substituted alkyl; R ⁴Be selected from alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical, be substituted heterocyclic radical and NR ²²R ²³, R wherein ²¹, R ²²And R ²³Be hydrogen, alkyl independently, be substituted alkyl, cycloalkyl or be substituted cycloalkyl; Perhaps R ²¹With R ²²Or R ²²With R ²³Be joined together to form the optional heterocyclic radical that replaces together with its bonded atom;

(d)-C (X ²)-N (R ³) CR ²R ^{2 '}C (=O) R ¹, X wherein ²Be selected from=O ,=S and=NR ¹¹, R wherein ¹¹Be hydrogen or alkyl; R ¹Be selected from-OR ⁷With-NR ⁸R ⁹, R wherein ⁷Be selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical; R ⁸And R ⁹As hereinbefore defined;

R ²And R ²' be independently selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical;

Perhaps defined R ²And R ²' together with the carbon atom of its side joint form cycloalkyl, be substituted cycloalkyl, heterocyclic radical or be substituted heterocyclic radical;

Perhaps R ²Or R ²' in one be hydrogen, alkyl or be substituted alkyl, and another person is together with the carbon atom of its side joint, together with R ⁷With the Sauerstoffatom of its side joint or together with R ⁸Be joined together to form heterocyclic radical or be substituted heterocyclic radical with the nitrogen-atoms of its side joint;

R ³Be selected from hydrogen and alkyl, or work as R ²And R ²' when forming ring not together and work as R ²Or R ²' and R ⁷Or R ⁸When not being joined together to form heterocyclic radical or being substituted heterocyclic radical, R then ³Nitrogen-atoms together with its side joint can be together with R ²And R ²' in one form heterocyclic radical together or be substituted heterocyclic radical;

(e)-C (X ²)-N (R ³) CR ²⁵R ²⁶R ²⁷, X wherein ²And R ³As hereinbefore defined, and R ²⁵, R ²⁶And R ²⁷Be independently selected from by alkyl, be substituted alkyl, aryl, be substituted aryl, heterocyclic radical, be substituted heterocyclic radical, heteroaryl and be substituted the group that heteroaryl is formed, or R ²⁵And R ²⁶Carbon atom together with its side joint forms cycloalkyl, is substituted cycloalkyl, heterocyclic radical or be substituted heterocyclic radical; With

(f) carboxylic acid isostere, wherein said isostere be not such as in (a)-(e) definition.

Description of drawings

Do not have

Embodiment

Definition

Should be appreciated that term as used herein only is for the purpose of describing specific embodiment and does not plan to limit the scope of the invention.To mention a plurality of terms in this specification sheets and the claims of enclosing, it should be defined as has following implication:

As used herein, " alkyl " be meant have 1 to 10 carbon atom, preferred 1 to 5 carbon atom and the more preferably univalent alkyl of 1 to 3 carbon atom.This term can be by such as illustrations such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyls.

" be substituted alkyl " and be meant and have 1 to 3 and preferred 1 to 2 substituent alkyl that is selected from by the following group that forms: alkoxyl group; be substituted alkoxyl group; acyl group; amido; acyloxy; amino; be substituted amino; aminoacyl; aryl; be substituted aryl; aryloxy; be substituted aryloxy; cyano group; halogen; hydroxyl; nitro; carboxyl; carboxyl ester; cycloalkyl; be substituted cycloalkyl; cycloalkenyl group; be substituted cycloalkenyl group; heteroaryl; be substituted heteroaryl; heterocyclic radical and be substituted heterocyclic radical.

" alkoxyl group " is meant " alkyl-O-" group, and it for example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy etc.

" be substituted alkoxyl group " and be meant " being substituted alkyl-O-" group.

" acyl group " be meant H-C (O)-, alkyl-C (O)-, be substituted alkyl-C (O)-, thiazolinyl-C (O)-, be substituted thiazolinyl-C (O)-, alkynyl-C (O)-, be substituted alkynyl-C (O)-, cycloalkyl-C (O)-, be substituted cycloalkyl-C (O)-, aryl-C (O)-, be substituted aryl-C (O)-, heteroaryl-C (O)-, be substituted heteroaryl-C (O), heterocyclic radical-C (O)-and be substituted heterocyclic radical-C (O)-group.

" amido " is meant-C (O) NR ^fR ^gGroup, wherein R ^fAnd R ^gBe independently selected from the group that forms by following: hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical, be substituted heterocyclic radical, and R wherein ^fAnd R ^gBe joined together to form heterocycle or be substituted heterocycle together with nitrogen-atoms.

" acyloxy " is meant alkyl-C (O) O-, is substituted alkyl-C (O) O-, thiazolinyl-C (O) O-, be substituted thiazolinyl-C (O) O-, alkynyl-C (O) O-, be substituted alkynyl-C (O) O-, aryl-C (O) O-, be substituted aryl-C (O) O-, cycloalkyl-C (O) O-, be substituted cycloalkyl-C (O) O-, heteroaryl-C (O) O-, be substituted heteroaryl-C (O) O-, heterocyclic radical-C (O) O-and be substituted heterocyclic radical-C (O) O-group.

" thiazolinyl " is meant the thiazolinyl that has 2 to 10 carbon atoms, preferably has 2 to 6 carbon atoms and more preferably have 2 to 4 carbon atoms and have at least 1 and preferred 1-2 the unsaturated site of thiazolinyl.

" be substituted thiazolinyl " and be meant and have 1 to 3 and preferred 1 to 2 substituent thiazolinyl that is selected from by the following group that forms: alkoxyl group, be substituted alkoxyl group, acyl group, amido, acyloxy, amino, be substituted amino, aminoacyl, aryl, be substituted aryl, aryloxy, be substituted aryloxy, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical, condition is that any hydroxyl replaces not and vinyl carbon atom side joint.

" alkynyl " is meant the alkynyl that has 2 to 10 carbon atoms, preferably has 2 to 6 carbon atoms and more preferably have 2 to 3 carbon atoms and have at least 1 and preferred 1-2 the unsaturated site of alkynyl.

" be substituted alkynyl " and be meant and have 1 to 3 and preferred 1 to 2 substituent alkynyl that is selected from by the following group that forms: alkoxyl group, be substituted alkoxyl group, acyl group, amido, acyloxy, amino, be substituted amino, aminoacyl, aryl, be substituted aryl, aryloxy, be substituted aryloxy, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical, condition is that any hydroxyl replaces not and acetylene carbon atom side joint.

" amino " is meant-NH ₂Group.

" be substituted amino " and be meant-NR ^hR ⁱGroup, wherein R ^hAnd R ⁱBe independently selected from the group that forms by following: hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical, be substituted heterocyclic radical, and R wherein ^hAnd R ⁱBe joined together to form heterocyclic radical or be substituted heterocyclic radical together with its bonded nitrogen, condition is R ^hAnd R ⁱBe not all hydrogen.Work as R ^hBe hydrogen and R ⁱDuring for alkyl, be substituted amino and be called as alkylamino in this article sometimes.Work as R ^hAnd R ⁱWhen all being alkyl, being substituted amino and being called as dialkyl amido in this article sometimes.

" aminoacyl " is meant-NR ^jC (O) alkyl ,-NR ^jC (O) be substituted alkyl ,-NR ^jC (O)-cycloalkyl ,-NR ^jC (O) be substituted cycloalkyl ,-NR ^jC (O) thiazolinyl ,-NR ^jC (O) be substituted thiazolinyl ,-NR ^jC (O) alkynyl ,-NR ^jC (O) be substituted alkynyl ,-NR ^jC (O) aryl ,-NR ^jC (O) be substituted aryl ,-NR ^jC (O) heteroaryl ,-NR ^jC (O) be substituted heteroaryl ,-NR ^jC (O) heterocyclic radical and-NR ^jC (O) is substituted heterocyclic radical group, wherein R ^jBe hydrogen or alkyl.

" aryl " or " Ar " is meant the monovalence aromatic carbon ring base with 6 to 14 carbon atoms of have monocycle (for example phenyl) or a plurality of condensed ring (for example naphthyl or anthryl), described condensed ring can be aromatic series or can be not for aromatic series (for example, 2-benzoxazoles quinoline ketone, 2H-1,4-benzoxazine-3 (4H)-ketone-7-bases etc.), condition is that tie point is the aromatic ring atom.Preferred aryl groups comprises phenyl and naphthyl.

" aralkyl " or " arylalkyl " is meant aryl-alkyl-group, and comprises for example benzyl.

" be substituted aryl " and be meant: hydroxyl through 1 to 3 and preferred 1 to 2 aryl that is selected from by the substituting group replacement of the following group that forms; acyl group; amido; acyloxy; alkyl; be substituted alkyl; alkoxyl group; be substituted alkoxyl group; thiazolinyl; be substituted thiazolinyl; alkynyl; be substituted alkynyl; amino; be substituted amino; aminoacyl; aryl; be substituted aryl; aryloxy; be substituted aryloxy; cycloalkyloxy; be substituted cycloalkyloxy; carboxyl; carboxyl ester; cyano group; mercaptan; cycloalkyl; be substituted cycloalkyl; halogen; nitro; heteroaryl; be substituted heteroaryl; heterocyclic radical; be substituted heterocyclic radical; heteroaryloxy; be substituted heteroaryloxy; heterocyclyloxy base and be substituted the heterocyclyloxy base.

" arylidene " and " being substituted arylidene " is meant divalent aryl as hereinbefore defined and is substituted aryl." phenylene " is optional 6 yuan of arylidene that replace, and for example comprises 1,2-phenylene, 1,3-phenylene and 1,4-phenylene.

" aryloxy " is meant aryl-O-group, and it comprises for example phenoxy group, naphthyloxy etc.

" be substituted aryloxy " and be meant and be substituted aryl-O-group.

" carboxyl " be meant-C (=O) OH or its salt.

" carboxyl ester " be meant-C (O) O-alkyl ,-C (O) O-be substituted alkyl ,-C (O) O-thiazolinyl ,-C (O) O-be substituted thiazolinyl ,-C (O) O-alkynyl ,-C (O) O-be substituted alkynyl ,-C (O) O-aryl ,-C (O) O-be substituted aryl ,-C (O) O-heteroaryl ,-C (O) O-be substituted heteroaryl ,-C (O) O-heterocyclic radical and-C (O) O-is substituted the heterocyclic radical group.Preferred carboxyl ester for-C (O) O-alkyl ,-C (O) O-be substituted alkyl ,-C (O) O-aryl and-C (O) O-is substituted aryl.

" cycloalkyl " is meant to have 3 to 10 carbon atoms and have monocycle or the polycyclic cycloalkyl that randomly comprises 1 to 3 plug-in carbonyl or thiocarbonyl group.Suitably cycloalkyl comprises for example adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ring octyl group, 3-oxo cyclohexyl etc.In a plurality of condensed ring, one or more rings can not be cycloalkyl (for example aryl, heteroaryl or heterocyclic radical), and condition is that tie point is the carboatomic ring atom of cycloalkyl.In one embodiment, cycloalkyl does not comprise 1 to 3 plug-in carbonyl or thiocarbonyl group.In another embodiment, cycloalkyl comprises 1 to 3 plug-in carbonyl or thiocarbonyl group.Should be appreciated that term " plug-in " is meant being connected of carboatomic ring atom of carbonyl or thiocarbonyl group and cycloalkyl.

" be substituted cycloalkyl " and be meant and have 1 to 5 substituent cycloalkyl that is selected from by the following group that forms: alkyl; be substituted alkyl; alkoxyl group; be substituted alkoxyl group; acyl group; amido; acyloxy; amino; be substituted amino; aminoacyl; aryl; be substituted aryl; aryloxy; be substituted aryloxy; cyano group; halogen; hydroxyl; nitro; carboxyl; carboxyl ester; cycloalkyl; be substituted cycloalkyl; heteroaryl; be substituted heteroaryl; heterocyclic radical and be substituted heterocyclic radical.

" cycloalkenyl group " is meant to have 5 to 10 carbon atoms and have monocycle or the polycyclic cycloalkenyl group that randomly comprises 1 to 3 plug-in carbonyl or thiocarbonyl group.Suitable cycloalkenyl group comprises for example cyclopentyl, cyclohexenyl, cyclooctene base, 3-oxo cyclohexenyl etc.In a plurality of condensed ring, one or more rings can not be cycloalkenyl group (for example aryl, heteroaryl or heterocyclic radical), and condition is that tie point is the carboatomic ring atom of cycloalkyl.In one embodiment, cycloalkenyl group does not comprise 1 to 3 plug-in carbonyl or thiocarbonyl group.In another embodiment, cycloalkenyl group comprises 1 to 3 plug-in carbonyl or thiocarbonyl group.Should be appreciated that term " plug-in " is meant being connected of carboatomic ring atom of carbonyl or thiocarbonyl group and cycloalkenyl group.

" be substituted cycloalkenyl group " and be meant and have 1 to 5 substituent cycloalkenyl group that is selected from by the following group that forms: alkoxyl group, be substituted alkoxyl group, acyl group, amido, acyloxy, amino, be substituted amino, aminoacyl, aryl, be substituted aryl, aryloxy, be substituted aryloxy, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical; condition is: with regard to hydroxyl substituent, tie point is not the vinyl carbon atom.

" cycloalkyloxy " is meant-the O-cycloalkyl.

" be substituted cycloalkyloxy " to be meant-O-is substituted cycloalkyl.

Term " guanidine radicals " is meant-NHC (=NH) NH ₂Group, and term " is substituted guanidine radicals " and is meant-NR ^pC (=NR ^p) N (R ^p) ₂, each R wherein ^pBe hydrogen or alkyl independently.

" halogen " or " halogen " is meant fluorine, chlorine, bromine and iodine and is preferably fluorine or chlorine.

" haloalkyl " is meant the alkyl that replaces through 1 to 5 halogen group.The example of haloalkyl is CF ₃

" heteroaryl " is to have 1 to 15 carbon atom, preferred 1 to 10 carbon atom in the finger ring and have 1 to 4 heteroatomic aromatic base that is selected from the group that is made up of oxygen, nitrogen and sulphur.Described heteroaryl be preferably have 1 to 15 carbon atom in the ring, preferred 1 to 10 carbon atom and have 1 to 4 heteroatomic aromatic base that is selected from the group that forms by oxygen, nitrogen and sulphur.Described heteroaryl can have monocycle (for example, pyridyl or furyl) or a plurality of condensed ring (for example, indolizine base or benzothienyl).Sulphur atom in the heteroaryl can be randomly through being oxidized to sulfoxide and sulfone part.

" be substituted heteroaryl " and be meant through 1 to 3 be selected from about being substituted the heteroaryl that substituting group that aryl defines identical substituting group group replaces.

When specific heteroaryl being defined as " being substituted " (for example, being substituted quinoline), should be appreciated that described heteroaryl contains 1 to 3 substituting group as indicated above.

" inferior heteroaryl " and " being substituted inferior heteroaryl " is meant divalence heteroaryl as hereinbefore defined and is substituted heteroaryl.

" heteroaryloxy " be meant-and O-heteroaryl groups and " being substituted heteroaryloxy " be meant-and O-is substituted heteroaryl groups.

" heterocycle " or " heterocycle shape " or " heterocyclic radical " are meant to have monocycle or a plurality of condensed ring, have 1 to 10 carbon atom and 1 to 4 heteroatomic saturated or unsaturated group that is selected from the group that is made up of nitrogen, sulphur or oxygen in the described ring, and described ring can randomly comprise 1 to 3 plug-in carbonyl or thiocarbonyl group.Described heterocyclic radical is preferably to have monocycle or a plurality of condensed ring, have 1 to 10 carbon atom and 1 to 4 heteroatomic saturated or unsaturated group that is selected from the group that is made up of nitrogen, sulphur or oxygen in described ring.Sulphur atom in the heteroaryl can be randomly through being oxidized to sulfoxide and sulfone part.

In a plurality of condensed ring, one or more rings can not be heterocycle (for example aryl, heteroaryl or cycloalkyl), and condition is that tie point is a heterocyclic atom.In one embodiment, heterocyclic radical does not comprise 1 to 3 plug-in carbonyl or thiocarbonyl group.In a preferred embodiment, heterocyclic radical comprises 1 to 3 plug-in carbonyl or thiocarbonyl group.Should be appreciated that term " plug-in " is meant being connected of carboatomic ring atom of carbonyl or thiocarbonyl group and heterocyclic radical.

" be substituted heterocyclic radical " and be meant through 1 to 3 with define the heterocyclic radical that identical substituting group replaces about being substituted cycloalkyl.The preferred substituents that is substituted heterocyclic radical comprises having 1 to 5 substituent heterocyclic radical that is selected from by the following group that forms: alkoxyl group, be substituted alkoxyl group, acyl group, amido, acyloxy, amino, be substituted amino, aminoacyl, aryl, be substituted aryl, aryloxy, be substituted aryloxy, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical.

When specific heterocyclic radical being defined as " being substituted " (for example being substituted morpholinyl), should be appreciated that described heterocycle contains 1 to 3 substituting group as indicated above.

The example of heterocycle and heteroaryl includes, but is not limited to azetidine, the pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indoline, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, the naphthyl pyridine, quinoxaline, quinazoline, cinnolines, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene, isoxzzole, Phenazoxine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1,2,3,4-tetrahydrochysene-isoquinoline 99.9,4,5,6,7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thio-morpholinyl (being also referred to as the thiomorpholine base), piperidyl, tetramethyleneimine, tetrahydrofuran base etc.

" heterocyclyloxy base " be meant-and O-heterocyclic radical group and " being substituted the heterocyclyloxy base " be meant-and O-is substituted the heterocyclic radical group.

Term " mercaptan " is meant-the SH group.

" isostere " is for having the differing molecular formula but represent the different compounds of same or similar characteristic.For instance, although tetrazolium has extremely different molecular formula with carboxylic acid, because the characteristic of tetrazolium simulation carboxylic acid, so tetrazolium is the isostere of carboxylic acid.Tetrazolium is a kind of in the multiple possible isostere alternative of carboxylic acid.Other carboxylic acid isostere that the present invention is contained comprises-COOH ,-SO ₃H ,-SO ₂HNR ^k,-PO ₂(R ^k) ₂,-CN ,-PO ₃(R ^k) ₂,-OR ^k,-SR ^k,-NHCOR ^k,-N (R ^k) ₂,-CON (R ^k) ₂,-CONH (O) R ^k,-CONHNHSO ₂R ^k,-COHNSO ₂R ^kWith-CONR ^kCN, wherein R ^kBe selected from hydrogen, hydroxyl, halogen, haloalkyl, thiocarbonyl group, alkoxyl group, alkene oxygen base, alkyl-aryloxy, aryloxy, alkoxy aryl, cyano group, nitro, imino-, alkylamino, aminoalkyl group, sulfenyl, sulfane base, alkyl sulfenyl, alkylsulfonyl, alkyl, alkenyl or alkynyl, aryl, aralkyl, cycloalkyl, heteroaryl, heterocycle and CO ₂R ^m, R wherein ^mBe hydrogen, alkyl or alkenyl.In addition, the carboxylic acid isostere can comprise 5-7 unit carbocyclic ring, or contains the CH that is under any chemically stable oxidation state ₂, O, S or N the 5-7 unit heterocycle of any combination, any atom in the wherein said ring structure randomly is substituted in one or more positions.The limiting examples of the preferred electron isostere that following structure contains for the present invention:

Atom in the wherein said ring structure can be randomly in one or more positions through R ^kReplace.The present invention's expection is when adding to chemical substituting group on the carboxylic acid isostere, and compound then of the present invention still keeps the characteristic of carboxylic acid isostere.The present invention's expection is worked as the carboxylic acid isostere and randomly is selected from R through one or more ^kPart when replacing, then described replacement can not be eliminated the carboxylic acid isostere bulk properties of The compounds of this invention.If the present invention's expection is R ^kSubstituting group will destroy the carboxylic acid isostere bulk properties of The compounds of this invention, will not allow one or more R on the carboxylic acid isostere so ^kSubstituent position is in the carboxylic acid isostere bulk properties that keeps The compounds of this invention or is necessary one or more atom places of carboxylic acid isostere property integrity for the formation The compounds of this invention.

" carboxylic acid bioisostere " is for showing as the compound of carboxylic acid isostere under biotic condition.

Other carboxylic acid isostere of special illustration or description is also contained in this specification sheets in the present invention.

" metabolite " is meant any derivative that produces behind throwing and the parent compound in individual body.Metabolite can be produced through various biochemical conversions (such as oxidation, reduction, hydrolysis or combination) in individual body by parent compound.Metabolite for example comprises oxide compound and demethylation derivative.

" thiocarbonyl group " is meant C (=S) group.

" pharmaceutically acceptable salt " is meant the pharmaceutically acceptable salt of compound, and described salt is derived from well-known organic and inorganic counter ion in multiple this technology, and it comprises for example sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium etc.; And when described molecule contains basic functionality the organic or inorganic hydrochlorate, such as hydrochloride, hydrobromate, tartrate, mesylate, acetate, maleate, oxalate etc.

" prodrug " is meant the modification of generally acknowledging in the industry that one or more functional groups are done, the metabolism in vivo of described functional group, thus compound of the present invention or its active metabolite are provided.These functional groups are well-known in this technology, and it comprises for hydroxyl and/or the amino acyl group that replaces; Phosplate, bisphosphate and triguaiacyl phosphate, one of them or above side joint hydroxyl have changed into alkoxyl group, have been substituted alkoxyl group, aryloxy or be substituted aryloxy etc.

" treatment " of " treatment " disease or disease is meant 1) prevent susceptible disease or do not show that as yet disease appears in the patient of disease symptoms; 2) suppress disease or block its development; Or 3) improve disease or cause that disease disappears." patient " is meant Mammals and comprises the mankind and non-human mammal.

" tautomer " is meant the alternatively form of the compound that the proton position is different, such as enol-keto tautomerism body and imine-enamine tautomerism body, or contain the tautomeric form (such as pyrazoles, imidazoles, benzoglyoxaline, triazole and tetrazolium) of the heteroaryl of the annular atoms that partly all is connected with ring-NH-part and ring=N-.

Unless otherwise mentioned, otherwise herein not clearly the substituent name of definition be the terminal portions by name functional group and name adjacent functional group to draw subsequently towards tie point.For instance, substituting group " aryl-alkoxy carbonyl " is meant (aryl)-(alkyl)-O-C (O)-group; Term " alkyl-aryloxy " is meant alkyl-aryl-O-group; Term " alkoxy aryl " is meant aryl-alkyl-O-group; " sulfane base " is meant the SH-alkyl; " alkyl sulfenyl " is meant alkyl-S-etc.Various substituting groups also can have the title that substitutes but be equal to.For instance, term 2-oxo-ethyl and term carbonyl methyl all refer to-C (O) CH ₂-group.

Should be appreciated that, above defined all be substituted in the group, this paper does not plan to comprise by defining (for example itself to have polymkeric substance that other substituent substituting group obtains again, be substituted aryl and have the aryl of being substituted as substituting group, and described substituting group itself replaces by being substituted aryl, and it is further by being substituted aryl replacement etc.).Under these situations, the maximum number of described replacement is 3.For instance, be substituted aryl and two other continuous replacements that are substituted aryl and be limited to-be substituted aryl-(being substituted aryl)-be substituted aryl.

Similarly, should be appreciated that above definition do not plan to comprise unallowed substitute mode (for example, through the methyl of 5 fluorine-based replacements or at the hydroxyl of alkene system or the undersaturated α of alkyne series position).This type of unallowed substitute mode is that the those skilled in the art is well-known.

Therefore, provide formula (I) compound or its pharmaceutically acceptable salt, ester, steric isomer, prodrug or tautomer:

Wherein:

Or

Among D or the E one is C-R ^aAnd another person among D or the E is S;

Z is selected from the group that is made up of following:

(a) carboxyl and carboxyl ester;

(b)-C (X ⁴) NR ⁸R ⁹, X wherein ⁴For=O ,=NH or=the N-alkyl, R ⁸And R ⁹Be independently selected from by hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted the group that heterocyclic radical is formed; Perhaps R ⁸And R ⁹Together with the nitrogen-atoms of its side joint-play the formation heterocycle, be substituted heterocycle, heteroaryl ring or be substituted the heteroaryl ring group;

(d)-C (X ²)-N (R ³) CR ²R ²C (=O) R ¹, X wherein ²Be selected from=O ,=S and=NR ¹¹, R wherein ¹¹Be hydrogen or alkyl; R ¹Be selected from-OR ⁷With-NR ⁸R ⁹, R wherein ⁷Be selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical; R ⁸And R ⁹As hereinbefore defined;

R ²And R ^{2 '}Be independently selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical;

Perhaps defined R ²And R ^{2 '}Carbon atom together with its side joint forms cycloalkyl, is substituted cycloalkyl, heterocyclic radical or be substituted heterocyclic radical;

Perhaps R ²Or R ^{2 '}In one be hydrogen, alkyl or be substituted alkyl, and another person is together with the carbon atom of its side joint, together with R ⁷With the Sauerstoffatom of its side joint or together with R ⁸Be joined together to form heterocyclic radical or be substituted heterocyclic radical with the nitrogen-atoms of its side joint;

R ³Be selected from hydrogen and alkyl, or work as R ²And R ^{2 '}When forming ring not together and work as R ²Or R ^{2 '}And R ⁷Or R ⁸When not being joined together to form heterocyclic radical or being substituted heterocyclic radical, R then ³Nitrogen-atoms together with its side joint can be together with R ²And R ^{2 '}In one form heterocyclic radical together or be substituted heterocyclic radical;

In another embodiment, provide have formula compound or its pharmaceutically acceptable salt or the tautomer of (Ia):

Wherein:

Y is selected from by being substituted aryl and being substituted the group that heteroaryl is formed;

X is independently selected from the group that is made up of amino, nitro, alkyl, haloalkyl and halogen;

T equals 0,1 or 2 integer;

Q is selected from the group that is made up of cyclohexyl and cyclopentyl;

R ¹²And R ¹³Be independently selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, alkoxyl group, be substituted alkoxyl group ,-(CH ₂) _0-3R ¹⁶With-NR ¹⁷R ¹⁸Or R ¹²And R ¹³Form the heterocycle that is substituted or is unsubstituted with its nitrogen-atoms that is connected, condition is R ¹²And R ¹³Be not all hydrogen; R wherein ¹⁶Be aryl, heteroaryl or heterocyclic radical; And R ¹⁷And R ¹⁸Be hydrogen or alkyl independently; Or R ¹⁷And R ¹⁸Be joined together to form heterocycle with 4 to 7 annular atomses together with the nitrogen-atoms that it connected;

Among A or the B one is C-R ^aAnd another person among A or the B is S;

R ^aBe selected from by hydrogen, alkyl and be substituted the group that alkyl is formed; And

Z is selected from the group that is made up of carboxyl, carboxyl ester and carboxylic acid isostere.

In other embodiments, the invention provides the compound of formula (Ib)-(Is):

Wherein Z, R ^aWith Y in the preamble formula (I) definition; And R ¹²And R ¹³Such as in the preamble formula (Ia) definition.

Among some embodiment of each, E is S in formula (I) and formula (Ia).In other embodiments, D is that CH and E are S.

In formula (I) and formula (Ia)-(Is) among some embodiment of each, in the time of suitably, R ^aBe hydrogen.In other embodiments, R ^aFor being substituted alkyl, being substituted amino or being substituted aminoalkyl group.In certain aspects, R ^aBe selected from following substituting group:

Among some embodiment of each, in the time of suitably, Q is cycloalkyl or is substituted cycloalkyl in formula (I) and formula (Ia)-(Is).In certain embodiments, Q is a cycloalkyl.In other embodiments, Q is a cycloalkenyl group.In another embodiment, Q is a cyclohexyl.In another embodiment, Q is a cyclohexenyl.In another embodiment, T is a cyclopentyl.

Among some embodiment of each, in the time of suitably, Z is carboxyl or carboxyl ester in formula (I) and formula (Ia)-(Is).In another embodiment, Z is selected from-C (=O) OH and-C (=O) OR ", wherein R " is an alkyl.In another embodiment, Z is selected from carboxyl, carboxylate methyl ester and carboxylic acid, ethyl ester.In another embodiment, Z is-C (=O) OH.

In another embodiment, Z is the carboxylic acid isostere.In another embodiment, the carboxylic acid isostere is the carboxylic acid bioisostere.In another embodiment, the carboxylic acid isostere is selected from 1H-tetrazolium-5-base and 5-oxo-4,5-dihydro-1,2,4-oxadiazoles-3-base.

In another embodiment, Z is-C (=O) NR ⁸R ⁹, R wherein ⁸Be hydrogen, and R ⁹Be selected from by alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted the group that heterocyclic radical is formed.At Z-C (=O) NR ⁸R ⁹And R ⁸Among another embodiment for hydrogen, R ⁹For being substituted alkyl.At Z-C (=O) NR ⁸R ⁹And R ⁸Be hydrogen and R ⁹In another embodiment that is substituted alkyl, be substituted alkyl and comprise 1 to 2 and be selected from by sulfonic acid (SO ₃H), carboxyl, carboxyl ester, amino, be substituted amino, aryl, be substituted aryl, heteroaryl and be substituted the substituting group of the group that heteroaryl forms.At Z-C (=O) NR ⁸R ⁹And R ⁸Be hydrogen and R ⁹In another embodiment that is substituted alkyl; be substituted alkyl and be selected from the group that forms by following: 3; the 4-dimethoxy-benzyl; 3; the 4-dihydroxy benzyl; 3-methoxyl group-4-hydroxybenzyl; 4-amino-sulfonyl benzyl; 4-methyl sulphonyl benzyl; (1-methyl-piperidines-3-yl) methyl; (1-methyl-tetramethyleneimine-3-yl) methyl; furans-2-ylmethyl; 6-picoline-2-ylmethyl; 2-(1-methyl-tetramethyleneimine-3-yl) ethyl; the 1-styroyl; 1-(3-p-methoxy-phenyl)-ethyl; 1-(4-p-methoxy-phenyl)-ethyl; N ', N '-dimethyl aminoethyl and 2-(1H-pyrazol-1-yl) ethyl.

In another embodiment, Z is selected from N-methylformamide, N, dinethylformamide base, N-sec.-propyl-formamido-, N-allyl group-formamido-and 5-hydroxyl-tryptophane-carbonyl.

In another embodiment, Z is-C (=O) NR ⁸R ⁹, R wherein ⁹For aryl or be substituted aryl.At Z-C (=O) NR ⁸R ⁹Another embodiment in, R ⁹For being substituted aryl.At Z-C (=O) NR ⁸R ⁹Another embodiment in, R ⁹Be selected from the group that forms by following: 7-hydroxyl naphthalene-1-base, 6-hydroxyl naphthalene-1-base, 5-hydroxyl naphthalene-1-base, 6-carboxyl naphthalene-2-base, (4-HOOCCH ₂-) phenyl, (3, the 4-dicarboxyl) phenyl, 3-carboxyl phenyl, 3-carboxyl-4-hydroxy phenyl and 2-xenyl.

In another embodiment, Z is-C (=O) NR ⁸R ⁹, R wherein ⁹For heteroaryl or be substituted heteroaryl.At Z-C (=O) NR ⁸R ⁹Another embodiment in, R ⁹For being substituted heteroaryl.At Z-C (=O) NR ⁸R ⁹And R ⁹In another embodiment that is substituted heteroaryl, be substituted heteroaryl and be selected from the group that forms by following: 4-methyl-2-oxo-2H-chromene-7-base, 1-phenyl-4-carboxyl-1H-pyrazoles-5-base, 5-carboxyl pyridine-2-base, 2-carboxyl pyrazine-3-base and 3-carboxy thiophene-2-base.

In another embodiment, Z is-C (=O) NR ⁸R ⁹, R wherein ⁹Be heterocyclic radical.At Z-C (=O) NR ⁸R ⁹And R ⁹Among another embodiment for heterocyclic radical, heterocyclic radical is N-morpholinyl, tetrahydrofuran base and 1,1-dioxo tetrahydro-thienyl.

In another embodiment, Z is-C (=O) NR ⁸R ⁹, R wherein ⁸And R ⁹Nitrogen-atoms together with its side joint forms heterocycle or is substituted heterocycle.At Z-C (=O) NR ⁸R ⁹And R ⁸And R ⁹Nitrogen-atoms together with its side joint forms among another embodiment of ring, heterocycle and be substituted heterocycle and comprise and contain 1 to 3 heteroatomic 4 yuan to 8 yuan ring.At Z-C (=O) NR ⁸R ⁹And R ⁸And R ⁹Among nitrogen-atoms one-optional another embodiment of heterocyclic that replaces of a formation together with its side joint, 1 to 3 heteroatoms comprises 1 to 2 nitrogen-atoms.At Z-C (=O) NR ⁸R and R ⁸And R ⁹Nitrogen-atoms together with its side joint forms among optional another embodiment of heterocyclic that replaces, heterocycle or be substituted that heterocycle is selected from by piperidines, is substituted piperidines, piperazine, is substituted piperazine, morpholinyl, be substituted morpholinyl, thio-morpholinyl and be substituted the group that thio-morpholinyl is formed, wherein said thiomorpholine basic ring or the described sulphur atom that is substituted the thiomorpholine basic ring randomly through oxidation so that sulfoxide and sulfone part to be provided.At Z-C (=O) NR ⁸R ⁹And R ⁸And R ⁹Nitrogen-atoms together with its side joint forms among optional another embodiment of heterocyclic that replaces, heterocycle or be substituted heterocycle and be selected from the group that forms by following: 4-hydroxy piperidine-1-base, 1,2,3,4-tetrahydrochysene-3-carboxyl-isoquinoline 99.9-2-base, 4-methylpiperazine-1-base, morpholine-4-base, thiomorpholine-4-base, 4-methyl-piperazine-1-base and 2-oxo-piperazinyl.

In another embodiment, Z is-C (X) N (R ³) CR ²R ²C (=O) R ¹

In another embodiment, Z is-C (O) NHCHR ²C (=O) R ¹

In another embodiment, as Z be-C (X) N (R ³) CR ²R ^{2 '}C (=O) R ¹Or-C (O) NHCHR ²C (=O) R ¹The time, R ²Be selected from by hydrogen, alkyl, be substituted alkyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl and be substituted the group that heteroaryl is formed.At Z be-C (X) N (R ³) CR ²R ^{2 '}C (=O) R ¹Or-C (O) NHCHR ²C (=O) R ¹Another embodiment in, R ²Be selected from by hydrogen, alkyl, be substituted alkyl, cycloalkyl and be substituted the group that cycloalkyl is formed.At Z be-C (X) N (R ³) CR ²R ^{2 '}C (=O) R ¹Or-C (O) NHCHR ²C (=O) R ¹Another embodiment in, R ²Be selected from the group that forms by following: hydrogen, methyl, 1-methyl-prop-1-base, sec-butyl, methylol, 1-hydroxyl second-1-base, 4-amino-normal-butyl, 2-carboxyl second-1-base, carboxymethyl, benzyl, (1H-imidazol-4 yl) methyl, (4-phenyl) benzyl, (4-phenylcarbonyl group) benzyl, cyclohexylmethyl, cyclohexyl, 2-methyl sulfenyl second-1-base, sec.-propyl, carbamyl methyl, 2-carbamyl second-1-base, (4-hydroxyl) benzyl and 3-guanidine radicals-n-propyl.

In another embodiment, as Z be-C (X) N (R ³) CR ²R ^{2 '}C (=O) R ¹Or-C (O) NHCHR ²C (=O) R ¹The time, R ¹Be selected from by hydroxyl, alkoxyl group, amino (N-morpholinyl), amino and be substituted the amino group that forms.At Z be-C (X) N (R ³) CR ²R ^{2 '}C (=O) R ¹Or-C (O) NHCHR ²C (=O) R ¹Another embodiment in, R ¹Be selected from by hydroxyl, alkoxyl group, amino (N-morpholinyl), amino and be substituted the amino group that forms, and R ²And R ³Bonded carbon atom and nitrogen-atoms are joined together to form heterocyclic radical or are substituted heterocyclic radical respectively together with it.At Z be-C (X) N (R ³) CR ²R ^{2 '}C (=O) R ¹Or-C (O) NHCHR ²C (=O) R ¹Another embodiment in, R ¹Be selected from by hydroxyl, alkoxyl group, amino (N-morpholinyl), amino and be substituted the amino group that forms, and R ²And R ³Bonded carbon atom and nitrogen-atoms are joined together to form heterocyclic radical or are substituted heterocyclic radical respectively together with it, described heterocyclic radical and be substituted heterocyclic radical and be selected from the group that forms by following: pyrrolidyl, 2-carboxyl-pyrrolidyl, 2-carboxyl-4-hydroxyl pyrrolidine base and 3-carboxyl-1,2,3,4-tetrahydroisoquinoline-3-base.

In another embodiment, Z is selected from 1-methane amide basic ring penta-1-base aminocarboxyl, 1-formamido--1-methyl-second-1-base aminocarboxyl, 5-carboxyl-1,3-dioxan-5-base aminocarboxyl, 1-(N-methylformamide base)-1-(methyl)-second-1-base aminocarboxyl, 1-(N, the dinethylformamide base)-1-(methyl)-second-1-base aminocarboxyl, 1-carboxyl-1-methyl-second-1-base aminocarboxyl, 1-(N-methylformamide base)-ring fourth aminocarboxyl, 1-formamido--ring fourth aminocarboxyl, 1-(N, the dinethylformamide base)-ring fourth aminocarboxyl, 1-(N-methylformamide base)-ring penta aminocarboxyl, 1-(N, dinethylformamide base)-ring penta aminocarboxyl, 1-(formamido-)-ring penta aminocarboxyl, 3-[N-(4-(thiazolamine-4-yl) phenyl) aminocarboxyl]-piperidines-3-base aminocarboxyl, 3-formamido--tetramethyleneimine-3-base aminocarboxyl, [1-(4-(vinylformic acid)-phenyl) aminocarboxyl)-ring fourth-1-yl] aminocarboxyl and [1-methyl isophthalic acid-(4-(vinylformic acid)-phenyl) aminocarboxyl)-second-1-yl] aminocarboxyl.

In another embodiment, Z is-C (O) NR ²¹S (O) ₂R ⁴At Z be-C (O) NR ²¹S (O) ₂R ⁴Another embodiment in, R ⁴Be selected from by alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl and be substituted the group that heteroaryl is formed.At Z be-C (O) NR ²¹S (O) ₂R ⁴Another embodiment in, R ⁴Be methyl; ethyl; sec.-propyl; propyl group; trifluoromethyl; 2; 2; the 2-trifluoroethyl; phenyl; benzyl; styroyl; the 4-bromophenyl; 4-nitrophenyl or 4-aminomethyl phenyl; the 4-p-methoxy-phenyl; the 2-amino-ethyl; 2-(dimethylamino) ethyl; 2-N-benzyloxy amino-ethyl; pyridyl; thienyl; 2-chlorothiophene-5-base; 2-methoxycarbonyl phenyl; naphthyl; the 3-chloro-phenyl-; the 2-bromophenyl; the 2-chloro-phenyl-; the 4-Trifluoromethoxyphen-l; 2; the 5-difluorophenyl; the 4-fluorophenyl; the 2-aminomethyl phenyl; 6-oxyethyl group benzo [d] thiazol-2-yl; the 4-chloro-phenyl-; 3-methyl-5-fluorobenzene is [b] thiophene-1-base also; 4-acetylamino phenyl; quinoline-8-base; the 4-tert-butyl-phenyl; cyclopropyl; 2; the 5-Dimethoxyphenyl; 2; 5-two chloro-4-bromo-thiene-3-yl-s; 2; 5-two chloro-thiene-3-yl-s; 2; the 6-dichlorophenyl; 1; 3-dimethyl-5-chloro-1H-pyrazoles-4-base; 3; 5-dimethyl isoxazole-4-base; benzo [c] [1; 2; 5] thiadiazoles-4-base; 2; the 6-difluorophenyl; 6-chloro-imidazo [2; 1-b] thiazole-5-base; 2-(methyl sulphonyl) phenyl; isoquinoline 99.9-8-base; 2-methoxyl group-4-aminomethyl phenyl; 1; 3; 5-trimethylammonium-1H-pyrazoles-4-base; 1-phenyl-5-methyl isophthalic acid H-pyrazoles-4-base; 2; 4,6-trimethylphenyl and 2-carbamyl-second-1-base.

In another embodiment, Z is selected from hydrogen, halogen, alkyl, alkoxyl group, amino, is substituted amino and cyano group.

In another embodiment, Z is-C (X ²)-N (R ³) CR ²⁵R ²⁶R ²⁷, X wherein ²And R ³As hereinbefore defined, and R ²⁵, R ²⁶And R ²⁷For alkyl, be substituted alkyl, aryl, be substituted aryl, heterocyclic radical, be substituted heterocyclic radical, heteroaryl and be substituted heteroaryl; Or R ²⁵And R ²⁶Carbon atom together with its side joint forms cycloalkyl, is substituted cycloalkyl, heterocyclic radical or be substituted heterocyclic radical.

In another embodiment, Z is selected from 1-(6-(3-carboxyl third-2-alkene-1-yl)-1H-benzo [d] imidazoles-2-yl) ring fourth aminocarboxyl; 3-(6-(3-carboxyl third-2-alkene-1-yl)-1H-benzo [d] imidazoles-2-yl)-1-methylpyrrolidin-3-aminocarboxyl; 1-(1-methyl-6-(3-carboxyl third-2-alkene-1-yl)-1H-benzo [d] imidazoles-2-yl) ring fourth aminocarboxyl; 1-(cumarone-2-yl)-5-carboxyl-ring fourth aminocarboxyl; 1-(2-methylthiazol-4-yl)-ring fourth aminocarboxyl; 1-(2-acetylamino-thiazole-4-yl)-ring fourth amino; 1-(2-methylamino-thiazole-4-yl)-ring fourth aminocarboxyl; 1-(2-ethyl thiazole-4-yl)-ring fourth aminocarboxyl and 1-(cyano group)-ring fourth aminocarboxyl.

In formula (I) and formula (Ia)-(Is) among other embodiment of each, in the time of suitably, Z be carboxyl, carboxyl ester, carboxylic acid isostere ,-C (O) NR ⁸R ⁹Or-C (O) NHS (O) ₂R ⁴, R wherein ⁸And R ⁹As hereinbefore defined, and R ⁴Be alkyl or aryl.In other embodiments; Z is carboxyl, carboxylate methyl ester, carboxylic acid, ethyl ester, 6-(β-D-glucuronic acid) ester, 1H-tetrazolium-5-base, 5-oxo-4; 5-dihydro-1; 2,4-oxadiazoles-3-base, N-2-cyano group-buserelin, N-2-(1H-tetrazolium-5-yl) buserelin, methyl sulphonyl aminocarboxyl, trifluoromethyl sulfonyl aminocarboxyl or phenyl sulfonyl amino carbonyl.In other embodiments, Z is a carboxyl.In other embodiments, Z is-C (=O) OH.

In formula (I) and formula (Ia)-(Is) among some embodiment of each, in the time of suitably, Z ¹Be selected from the group that forms by hydrogen, halogen, alkyl and haloalkyl.

Among some embodiment of each, in the time of suitably, R is C in formula (I) and formula (Ia)-(Is) _VH _2V-C (O)-OR ²³, wherein v is 1,2 or 3; And R ²³For hydrogen, alkyl or be substituted alkyl.At R is C _VH _2V-C (O)-OR ²³Another embodiment in, v is 1.At R is C _VH _2V-C (O)-OR ²³Another embodiment in, R is carboxymethyl or methyl carboxymethyl.

In another embodiment, R is a hydrogen.

In another embodiment, R is C _VH _2V-C (O)-NR ¹²R ¹³, wherein v is 1,2 or 3; R ¹²And R ¹³Be selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, alkoxyl group, be substituted alkoxyl group and-(CH ₂) _0-3R ¹⁶And R ¹⁶For aryl, heteroaryl, heterocyclic radical ,-NR ¹⁷R ¹⁸And R ¹⁷And R ¹⁸Be independently selected from hydrogen and alkyl, perhaps R ¹⁷And R ¹⁸Be joined together to form heterocycle with 4 to 7 annular atomses together with the nitrogen-atoms that it connected; Perhaps R ¹²And R ¹³Form heterocycle or be substituted heterocycle with its nitrogen-atoms that is connected, condition is R ¹²With R ¹³Be not alkoxyl group and/or be substituted alkoxyl group.In another embodiment, v is 1.At R is C _VH _2V-C (O)-NR ¹²R ¹³Another embodiment in, NR ¹²R ¹³Group is selected from N; N-dimethylamino-carbonyl methyl; [N-(4-hydroxyl-1; 1-dioxo tetrahydrochysene-3-thienyl) amino]-the carbonyl methyl; (cyclopropyl methylamino)-carbonyl methyl; (third-2-alkynes-1-base is amino)-carbonyl methyl; (2-(morpholinyl) second-1-base is amino)-carbonyl methyl; (phenyl sulfonyl amino)-carbonyl methyl; [N-benzylamino]-carbonyl methyl; (N-(4-methyl sulphonyl-benzyl) amino)-carbonyl methyl; (tryptophyl)-carbonyl methyl; (tyrosine)-carbonyl methyl; (N-(1-carboxyl third-1-base is amino)-carbonyl methyl; (N-(2-carboxyl second-1-yl)-amino)-carbonyl methyl; (N-(4-carboxyl benzyl)-amino)-carbonyl methyl; N-[3-(N '-(4-(vinylformic acid)-phenyl) formamido-) tetramethyleneimine-3-yl] amino-carbonyl methyl; N-[4-(N '-(4-(vinylformic acid)-phenyl) formamido-) piperidin-4-yl] amino-carbonyl methyl; [2-(N; the N-dimethylamino) second-1-base is amino]-the carbonyl methyl; [(1-(5-methyl-4H-1; 2; 4-triazole-3-yl) amino ethyl)]-the carbonyl methyl; (1-methyl isophthalic acid-[N-(1-methyl-2-carboxyl-1H-indoles-5-yl) aminocarboxyl] second-1-base amino-carbonyl methyl; [N-(1-methylpyrrolidin-3-base-ethyl)-amino]-carbonyl methyl; (1-methyl isophthalic acid-[N-(4-(vinylformic acid) phenyl) aminocarboxyl] second-1-base amino-carbonyl methyl; (1-methyl isophthalic acid-[N-(4-(2-carboxyl-furans-5-yl) phenyl) aminocarboxyl] second-1-base amino-carbonyl methyl; (1-methyl isophthalic acid-[N-(4-(4-carboxyl-thiazol-2-yl) phenyl) aminocarboxyl] second-1-base amino-carbonyl methyl; (2-(4-methylpiperazine-1-yl) second-1-base is amino)-carbonyl methyl; [(1-methylpyrrolidin-3-yl) methylamino]-carbonyl methyl; [N-(1-methyl piperidine-3-base-methyl)-amino]-carbonyl methyl; (1-piperidines-1-basic ring amyl group) methylamino]-the carbonyl methyl; (1-(ethanoyl)-tetramethyleneimine-2-ylmethyl) amino)-the carbonyl methyl; [(2-(N; the N-dimethylamino)-and carbonyl) methylamino]-the carbonyl methyl; [N-(1; 1-dioxo tetrahydrochysene-3-thienyl) methylamino]-the carbonyl methyl; (N-methyl-N-cyclohexyl-amino)-carbonyl methyl; (N-methyl-N-carboxymethyl-amino)-carbonyl methyl; [N-methyl-N-benzyl-amino]-carbonyl methyl; (N-methyl-N-(N '; N '-dimethylamino ethanoyl)-amino)-the carbonyl methyl; [N-methyl-N-phenyl-amino]-carbonyl methyl; (N-methyl-N-isopropyl propyl group-amino)-carbonyl methyl; (N-methyl-N-(N '-methyl piperidine-4-yl) amino)-the carbonyl methyl; [N-methyl-N-(1-methyl piperidine-4-yl) amino]-carbonyl methyl; [N-methyl-N-(1-methyl piperidine-4-base-methyl)-amino]-carbonyl methyl; [N-methyl-N-(1-methyl piperidine-3-base-methyl)-amino]-carbonyl methyl; [N-methyl-N-(1-methylpiperazine-2-base-methyl)-amino]-carbonyl methyl; [N-methyl-N-(5-methyl isophthalic acid H-imidazoles-2-ylmethyl)-amino]-carbonyl methyl; (N-methyl-N-[2-(hydroxyl) second-1-yl] amino)-the carbonyl methyl; (N-methyl-N-[2-(N '; N '-dimethylamino) second-1-yl] amino)-the carbonyl methyl; N-methyl-N-[2-(N '; N ' diethylamino) second-1-yl] amino)-the carbonyl methyl; (N-methyl-N-[2-(pyridine-2-yl) second-1-yl] amino)-the carbonyl methyl; (N-methyl-N-[2-(pyridin-4-yl) second-1-yl] amino)-the carbonyl methyl; [(1-(1 for N-methyl-N-; the 3-thiazol-2-yl) ethyl)-amino]-the carbonyl methyl; (N-methyl-N-[3-(N '; N '-dimethylamino) third-1-yl] amino)-the carbonyl methyl; (N-methyl-N-(1-carboxyl-2-methyl-prop-1-yl)-amino)-carbonyl methyl; (N-ethyl-N-propyl group-amino)-carbonyl methyl; (N-ethyl-N-[2-(methoxyl group) second-1-yl] amino)-the carbonyl methyl; (N-ethyl-N-[2-(N '; N '-diethylamino) second-1-yl] amino)-the carbonyl methyl; [7-methyl-2; 7-diaza spiro [4.4] ninth of the ten Heavenly Stems-2-yl]-the carbonyl methyl; (5-methyl-2; 5-diazabicyclo [2.2.1] heptan-2-yl)-the carbonyl methyl; (4-methyl isophthalic acid; 4-Diazesuberane-1-yl)-the carbonyl methyl; (piperidyl)-carbonyl methyl; (4-carboxyl-piperidyl)-carbonyl methyl; (3-carboxyl piperidyl)-carbonyl methyl; (4-hydroxy piperidine base)-carbonyl methyl; (4-(2-hydroxyl second-1-yl) piperidines-1-yl)-carbonyl methyl; [4-(N; the N-dimethylamino)-piperidines-1-yl]-the carbonyl methyl; (3-(N; the N-dimethylamino)-methyl piperidine-1-yl)-the carbonyl methyl; (2-(2-(N; the N-dimethylamino)-and second-1-yl) piperidines-1-yl)-the carbonyl methyl; [4-(4-methyl-4H-1; 2; 4-triazole-3-yl) piperidines-1-yl]-the carbonyl methyl; (4-pyrrolidyl-piperidyl)-carbonyl methyl; (3-pyrrolidyl-piperidyl)-carbonyl methyl; [4-(N; the N-diethylamino)-piperidines-1-yl]-the carbonyl methyl; (4-(azetidine-1-yl)-piperidines-1-yl)-carbonyl methyl; (4-(piperidines-1-yl)-piperidines-1-yl)-carbonyl methyl; (hexahydropyrrolo also [1; 2-a] pyrazine-2 (1H)-yl)-carbonyl methyl; [(2-(N; the N-dimethylamino)-and methyl) morpholinyl]-the carbonyl methyl; (3-5-dimethylated morpholinyl)-carbonyl methyl; (thio-morpholinyl)-carbonyl methyl; morpholinyl-carbonyl methyl; (pyrrolidyl)-carbonyl methyl; (2-carboxyl-tetramethyleneimine-1-yl)-carbonyl methyl; (2-(carboxyl)-4-hydroxyl-tetramethyleneimine-1-yl)-carbonyl methyl; (2-methane amide-tetramethyleneimine-1-yl)-carbonyl methyl; (2-(N; N-dimethylamino carbonyl)-tetramethyleneimine-1-yl)-the carbonyl methyl; (3-(N '; N '-dimethylamino)-tetramethyleneimine-1-yl)-the carbonyl methyl; (3-(N '; N '-diethylamino)-tetramethyleneimine-1-yl)-the carbonyl methyl; (3-(pyridin-3-yl)-tetramethyleneimine-1-yl)-carbonyl methyl; (2-pyridin-4-yl tetramethyleneimine-1-yl)-carbonyl methyl; piperazine-1-base-carbonyl methyl; (4-methylpiperazine base)-carbonyl methyl; (4-(carboxymethyl)-piperazine-1-yl)-carbonyl methyl; (4-(2-hydroxyl second-1-yl) piperazine-1-yl)-carbonyl methyl; (4-(sec.-propyl) piperazine-1-yl)-carbonyl methyl; (4-(2-methoxyl group second-1-yl) piperazine-1-yl)-carbonyl methyl; (4-(ethyl) piperazine-1-yl)-carbonyl methyl; (4-(N ', N '-dimethylamino ethanoyl)-piperazine-1-yl)-carbonyl methyl and (4-(6-methoxypyridine-2-yl) piperazine-1-yl)-carbonyl methyl.

In another embodiment, R is selected from morpholinyl carbonyl methyl, N, N-dimethylamino carbonyl methyl, (4-pyrrolidyl-piperidines-1-yl) carbonyl methyl, piperazinyl carbonyl methyl.In certain aspects, R is morpholinyl carbonyl methyl, N, the oxide compound of N-dimethylamino carbonyl methyl, (4-pyrrolidyl-piperidines-1-yl) carbonyl methyl, piperazinyl carbonyl methyl.

In another embodiment; R is selected from [(N; the N-dimethylamino) third-2-alkene-1-yl]-carbonyl methyl, (trifluoroacetic acid N; N-lupetidine-4-ammonium) ethanoyl, 2-(trifluoroacetic acid N; N-lupetidine-4-ammonium) morpholinyl ethanoyl, (2-(di-isopropyl) second-1-yl)-carbonyl methyl, (pyridin-4-yl carbonyl diazanyl)-carbonyl methyl, (N-(4-carboxyl benzyl)-amino) carbonyl diazanyl)-carbonyl methyl, (acetyl hydrazine)-carbonyl methyl, ((N ', N '-dimethylaminomethyl-carbonyl) diazanyl)-the carbonyl methyl.

In other embodiments, R is for being substituted alkyl, and the wherein said alkyl that is substituted is selected from the group that is made up of following: aminoalkyl group, be substituted aminoalkyl group, arylalkyl, be substituted arylalkyl, heteroarylalkyl, be substituted heteroarylalkyl, heterocyclic radical alkyl, be substituted the heterocyclic radical alkyl ,-CH ₂COOH and-CH ₂CONR ¹²R ¹³, R wherein ¹²And R ¹³Be independently selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, alkoxyl group, be substituted alkoxyl group ,-(CH ₂) _O-3R ¹⁶With-NR ¹⁷R ¹⁸, or R ¹²And R ¹³Form the heterocycle that is substituted or is unsubstituted with the nitrogen-atoms that it connected, condition is R ¹²With R ¹³Be not all hydrogen; R wherein ¹⁶Be aryl, heteroaryl or heterocyclic radical; And R ¹⁷And R ¹⁸Be hydrogen or alkyl independently, or R ¹⁷And R ¹⁸Be joined together to form heterocycle with 4 to 7 annular atomses together with the nitrogen-atoms that it connected.

In other embodiments, R is-CH ₂CONR ¹²R ¹³, and R ¹²Or R ¹³In at least one is alkyl, is substituted alkyl or heteroaryl.In certain aspects, R ¹²Or R ¹³In at least one is methyl, carboxymethyl, 2-hydroxyethyl, 2-morpholine-4-base ethyl or tetrazolium-5-base.In others, R is 1-methyl-piperidin-4-yl, 1-methyl-piperidines-3-ylmethyl and thiazol-2-yl carbamyl methyl.

In other embodiments, R is-CH ₂CONR ¹²R ¹³, and R ¹²And R ¹³Form the heterocycle that is substituted or is unsubstituted with the nitrogen-atoms that it connected.In certain aspects, R ¹²And R ¹³The tetramethyleneimine basic ring that forms the morpholinyl that is substituted or is unsubstituted, the piperidyl that is substituted or is unsubstituted or be substituted or be unsubstituted with the nitrogen-atoms that it connected.In others, the morpholinyl that is substituted or is unsubstituted, piperidyl or tetramethyleneimine basic ring are selected from the group that is made up of following: morpholinyl, 4-tetramethyleneimine-1-base-piperidyl, piperidyl, 4-hydroxy piperidine base, 4-carboxyl piperidyl, 4-dimethylamino piperidyl, 4-diethylamino piperidyl, 2-methylpyrrole alkyl, 4-morpholine-4-base-piperidyl, 3,5-dimethyl-morpholine-4-base, 4-methyl piperidine base.

In certain embodiments, R ¹²And R ¹³Form with the nitrogen-atoms that it connected and to be selected from following group: N; the N-dimethylamino; N-(4-hydroxyl-1; 1-dioxo tetrahydrochysene-3-thienyl) amino; the cyclopropyl methylamino; third-2-alkynes-1-base is amino; 2-(morpholinyl) second-1-base is amino; phenyl sulfonyl amino; the N-benzylamino; N-(4-methyl sulphonyl-benzyl) amino; tryptophyl; tyrosine; N-1-carboxyl third-1-base is amino; N-(2-carboxyl second-1-yl)-amino; N-(4-carboxyl benzyl)-amino; N-[3-(N '-(4-(vinylformic acid)-phenyl) formamido-) tetramethyleneimine-3-yl] amino; N-[4-(N '-(4-(vinylformic acid)-phenyl) formamido-) piperidin-4-yl] amino; 2-(N; the N-dimethylamino) second-1-base is amino; (1-(5-methyl-4H-1; 2; 4-triazole-3-yl) amino ethyl); 1-methyl isophthalic acid-[N-(1-methyl-2-carboxyl-1H-indoles-5-yl) aminocarboxyl] second-1-base is amino; N-(1-methylpyrrolidin-3-base-ethyl)-amino; 1-methyl isophthalic acid-[N-(4-(vinylformic acid) phenyl) aminocarboxyl] second-1-base is amino; 1-methyl isophthalic acid-[N-(4-(2-carboxyl-furans-5-yl) phenyl) aminocarboxyl] second-1-base is amino; 1-methyl isophthalic acid-[N-(4-(4-carboxyl-thiazol-2-yl) phenyl) aminocarboxyl] second-1-base is amino; 2-(4-methylpiperazine-1-yl) second-1-base is amino; (1-methylpyrrolidin-3-yl) methylamino; N-(1-methyl piperidine-3-base-methyl)-amino; (1-piperidines-1-basic ring amyl group) methylamino; 1-(ethanoyl)-tetramethyleneimine-2-ylmethyl) amino; (2-(N; the N-dimethylamino)-and carbonyl) methylamino; N-(1; 1-dioxo tetrahydrochysene-3-thienyl) methylamino; N-methyl-N-cyclohexyl-amino; N-methyl-N-carboxymethyl-amino; N-methyl-N-benzyl-amino; N-methyl-N-(N '; N '-dimethylamino ethanoyl)-amino; N-methyl-N-phenyl-amino; N-methyl-N-isopropyl propyl group-amino; N-methyl-N-(N '-methyl piperidine-4-yl) amino; N-methyl-N-(1-methyl piperidine-4-yl) amino; N-methyl-N-(1-methyl piperidine-4-base-methyl)-amino; N-methyl-N-(1-methyl piperidine-3-base-methyl)-amino; N-methyl-N-(1-methylpyrazine-2-base-methyl)-amino; N-methyl-N-(5-methyl isophthalic acid H-imidazoles-2-ylmethyl)-amino; N-methyl-N-[2-(hydroxyl) second-1-yl] amino; N-methyl-N-[2-(N '; N ' dimethylamino) second-1-yl] amino; N-methyl-N-[2-(N '; N '-diethylamino) second-1-yl] amino; N-methyl-N-[2-(pyridine-2-yl) second-1-yl] amino; N-methyl-N-[2-(pyridin-4-yl) second-1-yl] amino; (1-(1 for N-methyl-N-; the 3-thiazol-2-yl) ethyl)-amino; N-methyl-N-[3-(N '; N '-dimethylamino) third-1-yl] amino; N-methyl-N-(1-carboxyl-2-methyl-prop-1-yl)-amino; N-ethyl-N-propyl group-amino; N-ethyl-N-[2-(methoxyl group) second-1-yl] amino; N-ethyl-N-[2-(N '; N '-diethylamino) second-1-yl] amino; 7-methyl-2; 7-diaza spiro [4.4] ninth of the ten Heavenly Stems-2-base; 5-methyl-2; 5-diazabicyclo [2.2.1] heptan-2-base; the 4-methyl isophthalic acid; 4-Diazesuberane-1-base; piperidyl; 4-carboxyl-piperidyl; 3-carboxyl piperidyl; 4-hydroxy piperidine base; 4-(2-hydroxyl second-1-yl) piperidines-1-base; 4-(N; the N-dimethylamino)-piperidines-1-base; 3-(N; the N-dimethylamino)-methyl piperidine-1-base; 2-(2-(N; the N-dimethylamino)-and second-1-yl) piperidines-1-base; 4-(4-methyl-4H-1; 2; 4-triazole-3-yl) piperidines-1-base; 4-pyrrolidyl-piperidyl; 3-pyrrolidyl-piperidyl; 4-(N; the N-diethylamino)-piperidines-1-base; 4-(azetidine-1-yl)-piperidines-1-base; 4-(piperidines-1-yl)-piperidines-1-base; hexahydropyrrolo also [1; 2-a] pyrazine-2 (1H)-Ji; (2-(N; the N-dimethylamino)-and methyl) morpholinyl; 3; the 5-dimethylated morpholinyl; thio-morpholinyl; morpholinyl; pyrrolidyl; 2-carboxyl-tetramethyleneimine-1-base; 2-(carboxyl)-4-hydroxyl-tetramethyleneimine-1-base; 2-methane amide-tetramethyleneimine-1-base; 2-(N; N-dimethylamino carbonyl)-tetramethyleneimine-1-base; 3-(N '; N '-dimethylamino)-tetramethyleneimine-1-base; 3-(N '; N '-diethylamino)-tetramethyleneimine-1-base; 3-(pyridin-3-yl)-tetramethyleneimine-1-base; 2-pyridin-4-yl tetramethyleneimine-1-base; piperazine-1-base; 4-methylpiperazine base; 4-(carboxymethyl)-piperazine-1-base; 4-(2-hydroxyl second-1-yl) piperazine-1-base; 4-(sec.-propyl) piperazine-1-base; 4-(2-methoxyl group second-1-yl) piperazine-1-base; 4-(ethyl) piperazine-1-base; 4-(N ', N '-dimethylamino ethanoyl)-piperazine-1-base; 4-(6-methoxypyridine-2-yl) piperazine-1-base and 2-dimethylaminomethyl morpholine-4-base.

In certain embodiments, HET is selected from quinolinediyl and the quinolinediyl that is substituted.In another embodiment, HET is selected from quinolinediyl, inferior isoquinolyl, 7-methyl-quinolinediyl, 7-trifluoromethyl-quinolinediyl, 8-fluoro-quinolinediyl and 7-fluoro-quinolinediyl.In another embodiment, HET is that 2-[is substituted]-quinoline-6-base, 2-[be substituted]-7-methyl-quinolyl, 2-[be substituted]-7-fluoro-quinolyl, 2-[be substituted]-7-trifluoromethyl-quinolyl and 2-[be substituted]-8-fluoro-quinolyl.

In certain embodiments, HET is for randomly through (X) _tReplace

Wherein X, t, W ¹, W ³, W ⁴And W ⁵As previously defined.In certain aspects, W ¹Be nitrogen.In others, wherein HET is selected from the group that is made up of following:

With

In certain embodiments, HET is for randomly through (X) _t1 of replacement, the 4-phenylene, wherein X and t are as previously defined.

In certain embodiments, t is 0.

In another embodiment, t be 1 and X be amino, nitro, methyl or halogen.

In other embodiments, HET is selected from following group:

In certain embodiments, Y is aryl that is substituted or the heteroaryl that is substituted.

In certain embodiments, Y is selected from the group that is made up of following: be substituted xenyl; Be substituted phenyl; Randomly condense with phenyl ring and have 1,2 or 3 be independently selected from the group that is made up of N, O or S heteroatomic and be substituted 6 yuan of heteroaryl rings, wherein said heteroatoms N or S are randomly through oxidation; Randomly condense with phenyl ring and have 1,2 or 3 be independently selected from the group that is made up of N, O or S heteroatomic and be substituted 5 yuan of heteroaryl rings, wherein said heteroatoms N or S are randomly through oxidation.In certain embodiments, Y is substituted 5 yuan of heteroaryl rings for randomly condensing with phenyl ring and having 1,2 or 3 be independently selected from the group that is made up of N, O or S heteroatomic, and wherein said heteroatoms N or S are randomly through oxidation.

In another embodiment ,-Y is-Ar ¹-(G ¹) _q, Ar wherein ¹Be selected from arylidene and inferior heteroaryl, G ¹Be selected from halogen, hydroxyl, nitro, cyano group, alkyl, be substituted alkyl, alkoxyl group, be substituted alkoxyl group, acyl group, amido, aminoacyl, amino, be substituted amino, carboxyl and carboxyl ester; And q is 1 to 3 integer.At-Y be-Ar ¹-(G ¹) _qAnother embodiment in, Ar ¹Be selected from phenyl, thiazolyl, furyl, thienyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrryl, imidazolyl and pyrrolidyl.At-Y be-Ar ¹-(G ¹) _qAnother embodiment in, G ¹Be selected from bromine, chlorine, methyl, hydroxyl, methoxyl group, oxyethyl group, ethanoyl, acetamido, carboxyl and amino.In another embodiment; Y is selected from 2; 4-dimethylthiazole-5-base, 3-bromo-4-aminophenyl, 3-amido-4-hydroxyl-phenyl, 2-hydroxyl-6-methoxyl group-phenyl, 4-(acetylamino)-phenyl, 2; 4-dihydroxy phenyl, 2,4-dimethoxy-6-hydroxy phenyl and 7-hydroxyl benzofuran base.

In another embodiment, Y is-Ar ¹-Ar ²-, wherein said-Ar ¹-Ar ²-group is selected from the group that is made up of following :-aryl-aryl,-aryl-be substituted aryl,-be substituted aryl-aryl,-be substituted aryl-be substituted aryl,-aryl-heteroaryl,-aryl-be substituted heteroaryl,-be substituted aryl-heteroaryl,-be substituted aryl-be substituted heteroaryl, heteroaryl-aryl, heteroaryl-be substituted aryl, be substituted heteroaryl-aryl, be substituted heteroaryl-be substituted aryl,-aryl-cycloalkyl,-aryl-be substituted cycloalkyl,-be substituted aryl-cycloalkyl,-be substituted aryl-be substituted cycloalkyl,-aryl-heterocyclic radical, aryl-be substituted heterocyclic radical, be substituted aryl-heterocyclic radical and be substituted aryl-be substituted heterocyclic radical.

At Y be-Ar ¹-Ar ²-another embodiment in, described-Ar ¹-Ar ²-group is selected from the group that is made up of following: 4 '-chloro-4-methoxyl biphenyl-2-base; biphenyl-2-base; biphenyl-4-base; 4-amino-4 '-chlordiphenyl-2-base; 4 '-amino methyl-4-methoxyl biphenyl-2-base; 4-carbamyl-4 '-methoxyl biphenyl-2-base; 4-carbamyl-4 '-fluorine biphenyl-2-base; 4-carbamyl-4 '-methoxyl biphenyl-2-base; 4-carbamyl-4 '-nitrobiphenyl-2-base; 4-(carbamyl methyl-carbamyl) biphenyl-2-base; 4-(carbamyl methyl carbamyl)-4 '-chlordiphenyl-2-base; 4-carboxyl-4 '-chlordiphenyl-2-base; 3-carboxyl-4 '-methoxyl biphenyl-2-base; 4-carboxyl-4 '-methoxyl biphenyl-2-base; 4 '-carboxyl-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4-carboxyl methoxyl biphenyl-2-base; 4-carboxyl methoxyl group-4 '-chlordiphenyl-2-base; 4 '-chlordiphenyl-2-base; 4 '-chloro-4-chlordiphenyl-2-base; 4 '-chloro-4-(dimethyl aminoethyl carbamyl biphenyl-2-base; 4 '-chloro-4-(2-ethoxy ethoxy) biphenyl-2-base; 3 '-chloro-4 '-fluoro-4-methoxyl biphenyl-2-base; 4 '-chloro-4-fluorine biphenyl-2-base; 4 '-chloro-4-xenol-2-base; 3 '-chloro-4-methoxyl biphenyl-2-base; 4 '-chloro-4-methyl carbamyl biphenyl-2-base; 4 '-chloro-4-(2-methoxy ethoxy) biphenyl-2-base; 4 '-chloro-4-nitrobiphenyl-2-base; 4 '-chloro-4-(2-oxo-2-tetramethyleneimine-1-base oxethyl) biphenyl-2-base; 4 '-chloro-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4 '-chloro-4-(3-tetramethyleneimine-1-base propoxy-) biphenyl-2-base; 4 '-cyano group-4-methoxyl biphenyl-2-base; 3 '; 4 '-two chloro-4-methoxyl biphenyl-2-bases; 4; 4 '-dimethoxy-biphenyl-2-base; 3 ', 4 '-dimethoxy-4 '-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4 '-dimethylamino-4-methoxyl biphenyl-2-base; 4-(2-dimethyl aminoethyl carbamyl) biphenyl-2-base; 4 '-oxyethyl group-4-methoxyl biphenyl-2-base; 4 '-fluoro-4-methoxyl biphenyl-2-base; the 4-Hydroxybiphenyl; 4-methoxyl biphenyl base; 4-methoxyl group-4 '-xenol-2-base; 4-(2-methoxy ethoxy) biphenyl-2-base; 4-methoxyl group-4 '-methyl diphenyl-2-base; 4-methoxyl group-3 '-nitrobiphenyl-2-base; 4-methoxyl group-4 '-nitrobiphenyl-2-base; 4-methyl carbamyl biphenyl-2-base; 3 '-methyl-4-methoxyl biphenyl-2-base; 4 '-nitro-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4-(2-oxo-2-tetramethyleneimine-1-base oxethyl) biphenyl-2-base; 4-(3-tetramethyleneimine-1-base propoxy-) biphenyl-2-base and 4 ' trifluoromethyl-4-methoxyl biphenyl-2-base.

At Y be-Ar ¹-Ar ²-another embodiment in, described-Ar ¹-Ar ²-group is selected from the group that is made up of following: 4-(1H-imidazoles-1-yl) phenyl, 2-furans-2-base-5-p-methoxy-phenyl, 5-methoxyl group-2-thiophene-2-base phenyl, 2-(2,4-dimethoxypyridin-5-yl)-the 4-p-methoxy-phenyl, 2-(pyridin-4-yl) phenyl, 3-amino-5-phenyl thiophene-2-base, 5-(4-chloro-phenyl-)-2-methyl furan-2-base, 3-(4-chloro-phenyl-)-5-methyl isoxzzole-4-base, 2-(4-chloro-phenyl-)-4-methylthiazol-5-base, 3-(3,4-two chloro-phenyl) isoxzzole-5-base, 3,5-dimethyl-1-phenyl-1H-pyrazoles-4-base, 5-methyl-2-phenyl thiene-3-yl-and 1-phenyl-1H-pyrazoles-4-base.

At Y be-Ar ¹-Ar ²-another embodiment in, described-Ar ¹-Ar ²-group is selected from the group that is made up of following: 2-cyclohexyl-N, N-dimethylamino-carbonyl methyl-5-p-methoxy-phenyl and 4-morpholinyl phenyl.

In other embodiments, Y is selected from the group that is made up of following: be substituted quinolyl, be substituted benzofuryl, be substituted thiazolyl, be substituted furyl, be substituted thienyl, be substituted pyridyl, be substituted pyrazinyl, be substituted oxazolyl, be substituted isoxazolyl, be substituted pyrryl, be substituted imidazolyl, be substituted pyrrolidyl, be substituted pyrazolyl, be substituted isothiazolyl, be substituted 1,2,3-oxadiazoles base, be substituted 1,2, the 3-triazolyl, be substituted 1,3, the 4-thiadiazolyl group, be substituted pyrimidyl, be substituted 1,3, the 5-triazinyl, be substituted the indolizine base, the substituted indoles base, be substituted pseudoindoyl, be substituted indazolyl, be substituted benzothienyl, be substituted benzothiazolyl, be substituted purine radicals, be substituted quinolizinyl, be substituted quinolyl, the substituted isoquinoline base, be substituted the cinnolines base, be substituted phthalazinyl, be substituted quinazolyl, be substituted quinoxalinyl, be substituted 1,8-naphthyridinyl and be substituted pteridyl.In certain aspects, Y is independently selected from by the substituting group of the following group that forms through 1 to 3 and replaces: alkyl, haloalkyl, halogen, hydroxyl, nitro, cyano group, alkoxyl group, be substituted alkoxyl group, acyl group, amido, aminoacyl, amino, be substituted amino, carboxyl and carboxyl ester.In others, Y is 2,4-dimethylthiazole-5-base.

In certain embodiments, Y is selected from the corresponding Y group in the table 1.

In certain embodiments ,-Het-Y is:

Or

Preferred compound of the present invention or its pharmaceutically acceptable salt, part salt or tautomer comprise person described in the Table I down:

Table I

The present invention further provides any one metabolite of the compound of formula (I), (Ia)-(Is) or the compound in the table 1.In certain aspects, described metabolite is an oxide compound.

The invention still further relates to medical composition, it comprises the mixture of one or one or more these compounds in the compound described herein of pharmaceutically acceptable thinner and treatment significant quantity.

The invention further relates to the method for the mammiferous virus infection that is mediated by flaviviridae (such as HCV) to small part of treatment, described method comprise to be diagnosed as described virus infection or be in Mammals in the risk of the described virus infection of development throw with the compound described herein that comprises pharmaceutically acceptable thinner and treatment significant quantity in the medical composition of mixture of one or one or more these compounds.In another aspect, the invention provides compound of the present invention and be used to prepare the purposes that supplies treatment or prevent the medicine of described infection.In others, Mammals is human.

In another embodiment of the present invention, the treatment or the method for preventing mammiferous virus infection are provided, wherein with compound of the present invention and treatment significant quantity one or more to HCV have active medicament combination throw with.At the promoting agent of HCV comprise virazole (ribavirin), Levovirin (levovirin), Wei Lami pyridine (viramidine), thymosin, NS3 serpin and inosine list monophosphate dehydrogenase inhibitor, separately or with interferon-' alpha ', the polyoxyethylene glycol interferon-' alpha ' of virazole or Wei Lami pyridine combination.Other to HCV have active pharmacy optimization for separately or with the interferon-' alpha ' or the polyoxyethylene glycol interferon-' alpha ' of virazole or Wei Lami pyridine combination.

Universal synthesis method

Compound of the present invention can use the initial substance preparation by easy acquisition of following universal method and program.Should be appreciated that, when given typical case or preferred processing condition (being mol ratio, solvent, pressure of temperature of reaction, time, reactant etc.), unless otherwise mentioned, otherwise also can use other processing condition.Optimum reaction condition can change with employed specific reactants or solvent, but these conditions can be determined according to the optimization routine program by the those skilled in the art.

In addition, apparent as the those skilled in the art, the GPF (General Protection False base can be and prevents that the undesirable reaction of some functional group's experience institute is essential.Be used for the due care base of various functional groups in this technology as everyone knows and be used for the particular functional group is protected and de-protected felicity condition.For instance; T.W. Green (T.W.Greene) and P.G.M. watt (P.G.M.Wuts) now; protecting group in the organic synthesis (Protecting Groups in Organic Synthesis); the 3rd edition; Wei Li press (Wiley); New York (New York), 1999 and the reference wherein quoted in the kinds of protect base is described.

If compound of the present invention contains one or more chiral centres, these compounds can be through preparing or be separated into the mixture of pure stereoisomers (being indivedual enantiomers or diastereomer) or enrichment steric isomer so.Unless otherwise mentioned, otherwise all these steric isomers (with the mixture of enrichment steric isomer) all comprise within the scope of the invention.Pure stereoisomers (or mixture of enrichment steric isomer) can use in (for example) this technology well-known optical activity initial substance or stereoselectivity reagent to prepare.Perhaps, the racemic mixture of these compounds can use (for example) chiral column chromatography, chiral separation agent etc. to separate.

Flow process 1

In one embodiment; via transition metal-catalyzed type cross-coupling reaction preparation formula (I) compound as shown in above-mentioned flow process 1; wherein L and L ' are suitable cross coupling substituting group, and P ' is hydrogen, nitrogen-protecting group, or R and Z, D, E, R, Q, HET and Y are as previously defined.Usually, one among L or the L ' be based on Sn, B, Zr or Zn metal (for example-BOH ₂, Sn (CH ₃) ₃Deng) and L or L ' in another person be leavings group, such as halogen or sulfonate radical.Suitably halogen and sulfonate radical comprise Cl, Br, I ,-OSO ₂CF ₃With-OSO ₂CH ₃Suitably transition-metal catalyst comprises catalyzer based on Pd and Ni (Pd (PPh for example ₃) ₂Cl ₂, Pd[P (Ph ₃)] ₄Deng).In one embodiment, the L that had in 1.1 or 1.2 are-B (OH) ₂, and it is to prepare by the compound (wherein L or L ' they are halogen) with excessive two (neopentyl glycol foundation) two boron processing 1.1 or 1.2 under the situation of the dichloride triphenylphosphine palladium (II) that has catalytic amount.Under Suzuki coupling condition (Suzuki coupling condition), make another person (wherein L is halogen or sulfonate radical) coupling in gained boric acid and 1.1 or 1.2 to form formula (I) compound or intermediate 1.3.Suitable coupling condition comprises makes 1.1 and 1.2 containing Pd[P (Ph) ₃] ₄And NaHCO ₃Backflow methyl alcohol in the reaction 10 to 20 hours.When P ' is H or protecting group, removes protecting group and make gained NH group functionalization obtain compound (I) subsequently.The particular instance of this conversion is showed in the flow process 5.

Flow process 2

In one embodiment, synthetic compound 1.1 as shown in Scheme 2, and wherein for illustration purposes, D is CH, and E is S, and Z is COOP, and Q is a cyclohexyl, and P is hydroxyl protecting group (such as an alkyl), and P ' is that nitrogen-protecting group and L are halogen.Form nitro-compound 2.2 with nitric acid and vitriolic mixture process thiophene 2.1.The reduction nitro uses protecting group P ' (such as tertbutyloxycarbonyl) protection gained amine to obtain compound 2.3 subsequently.Available halogenating agent (such as N-bromosuccinimide, NBS) is handled thiophene 2.3 and is formed bromide 2.4.Make 2.4 to be exposed to trimethyl silane ethyl-acetylene, CuI and PdCl ₂(PPh ₃) ₂Obtain acetylene 2.5, it uses n-Bu subsequently ₄NF is handled and is exposed to microwave radiation forms 2.6.Next, under refluxad, compound 2.6 is reacted in ethanol with pimelinketone and sodium ethylate form tetrahydrobenzene 2.7, use H subsequently ₂And Pd (OH) ₂/ C or use such as reductive agents such as triethyl silicanes it is reduced into hexanaphthene 2.8.Then, can compound 2.8 is functionalized with the introducing radicals R, or can behind guard ring nitrogen, handle with halogenating agent (such as NBS), thereby form coupling collocation thing 2.9.

Flow process 3

Can be by the L '-HET-Y group 1.2 described in the well-known conventional procedure preparation flow 1 in this technology.A kind of universal method for preparing suitable HET-Y group for this convergent synthesis use of flow process 3 explanations.Flow process 3 is used aryl or the heteroaryl compound 3.1 through bromine and hydroxyl replacement, and it randomly further replaces (not shown) through one or more X groups.In case of necessity, well-known GPF (General Protection False base Pg protection hydroxyl in can this technology.By under conventional Suzuki condition, make 3.1 with boric acid 3.2 reaction formation compound 3.3, described boric acid 3.2 above the mode described in the flow process 1 by corresponding Y-Br compound.When Pg is not hydrogen, can remove protecting group by conventional procedure.Next, can under normal condition, the gained hydroxyl of compound 3.3 be changed into the compound 1.2 of the coupling step that is used for flow process 1.

Flow process 4 explanations hereinafter are suitable for carrying out with compound 1.1 preparation of the quinolyl HET-Y group with bromo of Suzuki coupling.Should be appreciated that this quinolyl is only for being described for illustration purposes.

Flow process 4

In flow process 4, under normal condition, the Sodium Nitrite of use equimolar amount, excessive HBr and the cupric bromide of catalytic amount change into corresponding bromo-2-methyl-oil of mirbane (compound 4.2) with commercially available amino-2-methyl-4-oil of mirbane (compound 4.1).Preferably under about-10 ℃ to 10 ℃ temperature by making compound 4.1 and excessive aqueous solution of hydrogen bromide (for example, 48%HBr) be combined in the inert solvent and react.The Sodium Nitrite of the equimolar amount that is dissolved in the water is slowly joined in the reaction mixture, keep temperature of reaction simultaneously.Then with solid brominated cuprous the joining in the reaction mixture of catalytic amount, and make reaction mixture be warmed up to temperature a little less than room temperature.Monitoring reaction shows to react and finishes till the nitrogen effusion stops.After this, can pass through routine techniques (such as evaporation, extraction, precipitation, filtration, chromatogram etc.) separating obtained product bromo-2-methyl-oil of mirbane (compound 4.2); Perhaps not purified and/or separation is about to it and is used for next step.

The suitable example of compound 4.1 comprises such as 2-nitro-3-monomethylaniline, 4-methyl-3-nitro aniline (all available from A De Ritchie chemical company (Aldrich Chemical Company), Milwaukee city (Milwaukee), Wisconsin State (Wisconsin), the U.S. (USA)) and 3-methyl-4-N-methyl-p-nitroaniline commercially available variants such as (available from Lancaster Synesis Company (LancasterSynthesis Inc.)).

Next, by making compound 4.2 and excessive N, dinethylformamide dimethylacetal (compound 4.3) reacts and compound 4.2 is changed into (e)-2-(bromo-2-nitrophenyl) vinyl-dimethyl amine (compound 4.4).Described reaction is carried out in such as appropriate solvents such as DMF under inert atmosphere usually.This reaction is preferably carried out to about 160 ℃ high temperature at about 100 ℃.Sustained reaction is till it is finished in fact, and this usually occurs in about 1 hour to 6 hours.After reaction is finished, can pass through the separating obtained product of routine techniques (such as evaporation, extraction, precipitation, filtration, chromatogram etc.); Perhaps not purified and/or separation is about to it and is used for next step.

Via making (E)-2-(bromo-2-nitrophenyl) vinyl-dimethyl amine (compound 4.4) contact the oxidation of carrying out compound 4.4, provide bromo-2-nitrobenzaldehyde with a large amount of excessive sodium periodates.This reaction is carried out in inert diluent (such as the aqueous mixture of tetrahydrofuran (THF), dioxan etc.) usually.This reaction preferably under envrionment conditions, carry out and sustained reaction till it is finished in fact, this usually occurs in about 0.5 hour to 6 hours.After reaction is finished, can pass through routine techniques (such as evaporation, extraction, precipitation, filtration, chromatogram etc.) separating obtained product bromo-2-nitrobenzaldehyde (compound 4.5); Perhaps not purified and/or separation is about to it and is used for next step.

The conventional reduction of compound 4.5 provides corresponding bromo-2-aminobenzaldehyde (compound 4.10).

By individually bromo-5-methoxy benzoyl chloride (compound 4.7) (available from plum cloth Ritchie company (Maybridge)) being changed into corresponding bromo-3-ethanoyl-anisole (compound 4.8) with the zinc methide reaction.Reaction is carried out in suitable inert diluent (such as benzene,toluene,xylene etc.) usually.But because the zinc methide spontaneous combustion, so zinc methide preferably is present in the solvent before adding compound 4.7.Reaction preferred at first approximately-10 ℃ carry out to about 10 ℃ temperature and make it slowly reach room temperature then.Sustained reaction is till it is finished in fact, and this took place in about 0.2 hour to 2 hours usually.After reaction is finished, can pass through routine techniques (such as evaporation, extraction, precipitation, filtration, chromatogram etc.) separating obtained product bromo-3-ethanoyl-methoxyl group-benzene (compound 4.8); Perhaps not purified and/or separation is about to it and is used for next step.

Perhaps; can be by corresponding commercially available bromo-5-methoxybenzoic acid (such as 2-bromo-5-methoxybenzoic acid (available from A De Ritchie chemical company (Aldrich Chemical Company); Milwaukee city (Milwaukee); Wisconsin State (Wisconsin), the U.S. (USA))) prepare bromo-5-methoxy benzoyl chloride (compound 4.7) by changing into acyl halide.Can prepare acyl halide with inorganic acyl halide (such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride) or preferred under normal condition, the contact by making carboxylic acid with oxalyl chloride.This reaction uses the inorganic acyl halide of about 1 to 5 molar equivalent or oxalyl chloride separately or carried out in inert solvent (such as methylene dichloride or tetracol phenixin) about 1 hour to about 48 hours usually under about 0 ℃ of temperature to about 80 ℃ of scopes.Also can use catalyzer in this reaction, such as DMF.

Via the Suzuki condition of routine, make commercially available chlorophenylboronic acid (compound 4.9) and compound 4.8 couplings so that the 3-ethanoyl anisole (compound 4.6) that replaces through chloro-phenyl-to be provided.2-, 3-and 4-chlorophenylboronic acid are available from A De Ritchie chemical company (Aldrich Chemical Company), together above.

Subsequently, under condensation condition, make compound 4.6 and compound 4.10 couplings so that 2-dibenzyl-6-bromoquinoline (compound 4.11) to be provided.This reaction preferably under the situation that has suitable alkali (such as potassium hydroxide), the compound 4.6 by making about stoichiometric amount in inert atmosphere with 4.10 both in suitable inert diluent (such as ethanol, Virahol etc.), make up and carry out.Reaction preferably about 70 ℃ carry out to about 100 ℃ temperature and sustained reaction till it is finished in fact, this took place in about 2 hours to 16 hours usually.After reaction is finished, can pass through the separating obtained product compound 4.11 of routine techniques (such as evaporation, extraction, precipitation, filtration, chromatogram etc.); Perhaps not purified and/or separation is about to it and is used for next step.

Flow process 5

Except that the synthesis method described in the flow process 1, also can be by other method preparation formula (I) compound.Flow process 5 is showed a kind of these class methods, and wherein for illustration purposes, Z is COOH, and D is CH, and E is S, and Q is a cyclohexyl, and Ra and HET-Y group are as about described in the compound 5.14.Use blue moral (Friedlander) condition of Fred, make compound 5.1 and commercially available (A De Ritchie (Aldrich)) 5.2 condensations to form quinoline 5.3.One example of described condition is provided in hereinafter the example 2.Use known method, corresponding pure 5.4 such as compound 5.3 being changed into lithium aluminum hydride, use Dai Si-Martin (Dess-Martin) reagent that it is reoxidised into aldehyde 5.5 subsequently.By commercially available thiophene 5.6 being changed into 5.7 with nitric acid/vitriolization.Under the situation of the tetramethyleneimine that has catalytic amount, compound 5.7 is refluxed to form nitro-alkene 5.8 in MeOH with 5.5 subsequently.Next, compound 5.8 is refluxed to obtain Thienopyrroles derivative 5.9 with triethyl-phosphite.As in the flow process 2, introduce cyclohexyl ring by heating 5.9 under the situation that has acetate, diacetyl oxide and phosphoric acid with pimelinketone, obtain 5.10.Obtain 5.11 with triethyl silicane reducing compound 5.10.By use the standard alkylation conditions make 5.11 with commercially available 5.12 in DMF reaction introduce the acetamido part to form 5.13, make its saponification obtain required product 5.14 with the LiOH aqueous solution.

Flow process 6

In another embodiment; synthesis type (I) compound as shown in Scheme 6; wherein for illustration purposes; D is S, and E is CH, and Z is COOP; Q is a cyclohexyl; P is hydroxyl protecting group (such as an alkyl), and P ' is a nitrogen-protecting group, L ' be leavings group (such as halogen) and HET and Y as previously defined.Under situation about existing, compound 6.1 and methyl-cyanacetate are reacted to form alkylate 6.2 such as alkali such as diisopropylethylamine.Be exposed to HCl with 6.2 and obtain pyrroles 6.3, subsequently can be by reacting the pyrroles (such as 6.4) who converts it into through protection with bromotoluene and NaH, wherein P ' is a benzyl.Next, such as ester 6.4 being changed into aldehyde 6.5: be reduced into corresponding alcohol with diisobutyl aluminium hydride with 6.4, use oxygenant subsequently (such as (n-Pr) through two step programs ₄N RuO ₄/ N-methylmorpholine N-oxide compound) it is oxidized to aldehyde 6.5.Aldehyde 6.5 is reacted in THF with Methyl Thioglycolate and potassium tert.-butoxide obtain compound 6.6, can introduce cyclohexyl with similar mode described in the flow process 5 and partly make it functionalized to obtain 6.7.Equally, P ' protecting group can be removed and can described in flow process 5, introduce the R group to obtain formula (I) compound in 6.7.

Flow process 7

Flow process 7 explanations are by making the synthetic of nitro-compound 7.3 and the formed intermediate 7.8 of aldehyde 7.6 couplings.Under suitable nitration condition,, make its esterification subsequently to obtain intermediate ester 7.3 such as by making 7.1 nitrated formation acid 7.2 in the solution that thiophene 7.1 is joined diacetyl oxide and nitric acid.Coupling collocation thing 7.6 is by the 7.4 initial preparations of 2-chloro-6-toluquinoline, makes 7.4 halogenations obtain the mixture 7.5 of single bromide and dibromide after handling through suitable halide reagent (such as NBS, i.e. N-bromosuccinimide).Subsequently, under the situation that has amine (such as vulkacit H), described mixture is refluxed in such as aqueous solvents such as 50% aqueous ethanolic solutions, after acid treatment, obtain aldehyde 7.6.Nitro-compound 7.3 and aldehyde 7.6 are refluxed in being added with the alcohol solvent (such as methyl alcohol) of the amine of catalytic amount (such as tetramethyleneimine) together obtain alkene 7.7, handle the Thienopyrroles 7.8 that described alkene forms cyclisation with triethyl-phosphite subsequently.The details of preparation 7.8 is provided in the example 4.

Flow process 8

Flow process 8 explanations are followed the method described in the flow process 5 and are used intermediate 7.8 preparation compound 8.2-8.6.

Flow process 9

Flow process 8 explanations are followed the method preparation described in the above-mentioned flow process such as 9.3 compounds such as grade.One example of synthetic compound 9.3 (wherein R ' and R " form cyclic group together) is provided in example 9 and the example 10.

Dispensing and medical composition

The invention provides and have antiviral (comprising flaviviridae) active compounds such as hepatitis C virus.Compound of the present invention suppresses virus replication by suppressing to duplicate the enzyme (comprising RNA RNA-dependent polysaccharase) that is involved.It also can suppress other enzyme of being utilized in the active of flavivirus or the propagation.

In general, compound of the present invention will by any for the acceptable dispensing pattern of the medicament that is used for similar effectiveness with treat effectively throw most with.The actual amount of The compounds of this invention (being activeconstituents) will be decided on multiple factor, such as the severity of the disease of desire treatment, individual age effectiveness, dosing way and form and the other factors with relative healthy state, employed compound.Described medicine can throw in one day with once more than, be preferably once a day or twice.

The treatment significant quantity of The compounds of this invention can be in about 0.01 to 50 milligram of per kilogram recipient body weight every day, preferably about 0.01-25 milligram/kg/day, more preferably from about in the scope of 0.1 to 10 milligram/kg/day.Therefore, for concerning people's dispensing of 70kg, dosage range the best is about 7-70mg every day.

The invention is not restricted to any particular composition or medical supporting agent, thereby can change.In general, compound of the present invention will with the medical composition form by in the following approach any throw with: per os, general (for example in skin, nose or) through suppository or non-through intestines (for example intramuscular, intravenously or subcutaneous) throw with.Preferred dosing mode can be oral according to convenient every day of the dosage that ailing degree is adjusted for using.Composition can adopt the form of tablet, pill, capsule, semisolid, powder, slowly-releasing composite, solution, suspension, elixir, aerosol or any other appropriate combination thing.Another is thrown and the optimal way of compound of the present invention is suction.

The selection of composite is decided on multiple factor, such as the bioavailability of medicine throwing and pattern and drug substance.For sending, described compound can be deployed into liquid solution, suspension, aerosol propellant or dry powder and be loaded in the suitable divider for dispensing via suction.There is some types medical suction apparatus: atomizer sucker, metered-dose inhaler (MDI) and Diskus (DPI).Sprayer device produces high velocity air, and it makes therapeutical agent (it is deployed into liquid form) spray with mist and is brought in patient's the respiratory tract.MDI is generally the composite with the pressurized gas encapsulation.After the actuating, described device provides the reliable method of throwing with quantitative pharmacy thus via the therapeutical agent of pressurized gas discharge metered amount.DPI distributes the therapeutical agent that is the free flowing powder form, and described powder can be scattered in patient's the suction air-flow through described device in the patient respiratory process.Be the flowing powder that gains freedom, with therapeutical agent with allocate such as vehicle such as lactose.The therapeutical agent of metered amount is stored and utilizes each distribution that activates with capsule form.

Recently, based on the pharmaceutical formulation that can increase the principle of bioavailability by increasing surface-area (promptly reducing particle diameter), develop the medicine that is particularly useful for showing bad bioavailability.For instance, United States Patent (USP) the 4th, 107, No. 288 descriptions have 10 to 1, the particulate pharmaceutical formulation in the 000nm size range, wherein active substance is to be stated from the macromolecules cross-linking matrix.United States Patent (USP) the 5th, 145, describe the manufacturing of pharmaceutical formulation for No. 684, wherein under having the situation of coating materials, drug substance is ground into nano particle (median size is 400nm) and subsequently it is scattered in the liquid medium to obtain representing the pharmaceutical formulation of significantly high bioavailability.

Composition generally comprises The compounds of this invention and at least a pharmaceutically acceptable vehicle.Acceptable vehicle should be nontoxic, help to offer medicine and the treatment benefit of the compound of being advocated is had no adverse effect.This type of vehicle can be any solid, liquid, semisolid or be the common available gaseous state of those skilled in the art vehicle for the situation of aerosol combination.

The solid pharmaceutical vehicle comprises starch, Mierocrystalline cellulose, talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, Magnesium Stearate, sodium stearate, glyceryl monostearate, sodium-chlor, skimmed milk powder etc.Liquid and semi-solid state vehicle can be selected from glycerine, propylene glycol, water, ethanol and various oil, comprises the oil in oil, animal oil, vegetables oil or synthetic source, for example peanut oil, soybean oil, mineral oil, sesame wet goods.The preferred liquid carrier that is particularly useful for Injectable solution comprises water, physiological saline, the dextrose aqueous solution and glycols.

Can use pressurized gas to disperse the The compounds of this invention of aerosol form.The rare gas element that is applicable to this purpose is nitrogen, carbonic acid gas etc.Other suitable medical vehicle and its composite are described in Lei Mingdun medical science (Remington ' sPharmaceutical Sciences), E.W. Martin (E.W.Martin) compiles (mark publishing company (Mack PublishingCompany), the 18th edition, 1990) in.

The amount of compound can change in the employed gamut of those skilled in the art in the composite.Described composite will contain the The compounds of this invention that accounts for the about 0.01-99.99 wt% of total composite in weight percent (wt%) usually, and surplus is one or more suitable medical vehicle.Described compound preferably exists with the content of about 1-80 wt%.Representative pharmaceutical formulation is described in hereinafter the composite example part.

In addition, the present invention relates to a kind of medical composition, it comprises the The compounds of this invention for the treatment of significant quantity and treats the promoting agent of the another kind of significant quantity at RNA RNA-dependent virus (and especially at HCV).To HCV have that active medicament comprises that (but being not limited to) virazole, Levovirin, Wei Lami are fixed, the combination of combination, interferon-' alpha ' and the Levovirin of combination, polyoxyethylene glycol interferon-' alpha ' and the virazole of thymosin, HCV NS3 serpin or inosine list monophosphate dehydrogenase inhibitor, interferon-' alpha ', polyoxyethylene glycol interferon-' alpha ' (peginterferon-α), interferon-' alpha ' and virazole and the combination of polyoxyethylene glycol interferon-' alpha ' and Levovirin.Interferon-' alpha ' includes, but is not limited to recombinant interferon-α 2a (such as available from Roche Holding Ag (Hoffman-LaRoche), nanotesla interests (Nutley), Wellferon (ROFERON) Interferon, rabbit in new damp two states (NJ)), interferon-' alpha ' 2b is (such as available from Schering Corp (ScheringCorp.), triumphant Neil Butterworth city (Kenilworth), New Jersey (New Jersey), Intron A (Intron-A) Interferon, rabbit of the U.S. (USA)), Interferon alfacon-1 and purified interferon-' alpha ' product.Please stop gram (S.A.Raybuck) about virazole and its active discussion referring to J.O. Saunders (J.O.Saunders) and S.A. thunder at HCV, " inosine list phosphate dehydrogenase: the Consideration in structure, kinetics and the treatment potentiality " (" Inosine MonophosphateDehvdrogenase:Consideration of Structure; Kinetics and Therapeutic Potential; ") medical chemistry annual report (Ann.Rep.Med.Chem.) 35: 201-210 (2000).

To hepatitis C virus have active medicament also comprise suppress that HCV proteolytic enzyme, HCV polysaccharase, HCV helicase, HCV NS4B albumen, HCV enter, HCV assembles, HCV disengages, HCV NS5A albumen and inosine 5 '-medicament of single phosphate dehydrogenase.Other medicament comprises the nucleoside analog that is used for the treatment of the HCV infection.Other compound comprises those compounds that disclosed in the reference that WO 2004/014313 and WO 2004/014852 and this paper quoted.The mode of asking case WO 2004/014313 and WO 2004/014852 to quote all in full in the patent is incorporated herein.

Specific antiviral agent comprises IFN-ω (biological medicine company (BioMedicines Inc.)), BILN-2061 (Boehringer Ingelheim (BoehringerIngelheim)), Sa rice Qu Er (Summetrel) (many pharmacy of grace parent corporation (EndoPharmaceuticals Holdings Inc.)), Wellferon A (Roferon A) (Roche Holding Ag (F.Hoffman-LaRoche)), Pai Luoxin (Pegasys) (Roche Holding Ag (F.Hoffman-La Roche)), Pai Luoxin/virazole (Roche Holding Ag (F.Hoffman-La Roche)), Sai Er Sept (CellCept) (Roche Holding Ag (F.Hoffman-La Roche)), Wellferon (Wellferon) (GlaxoSmithKline PLC (GlaxoSmithKline)), A Er interferon-' alpha ' (Albuferon-α) (human genome scientific ﹠ technical corporation (Human Genome Sciences Inc.)), Levovirin (Ai Xin pharmacy (ICNPharmaceuticals)), IDN-6556 (Acton pharmacy (Idun Pharmaceuticals)), IP-501 (Yin Deweisi pharmacy (Indevus Pharmaceuticals)), Ai Keting (Actimmune) (Ying Temiuen company (InterMune Inc.)), Infergen A (Infergen A) (Ying Temiuen company (InterMune Inc.)), ISISl 4803 (Yi Si drugmaker (ISISPharamceuticals Inc.)), JTK-003 (Japan Tobacco Inc (JTI) (Japan Tobacco Inc.)), Pai Luoxin/Sai Pulin (Ceplene) (Maxime's pharmacy (Maxim Pharmaceuticals)), Sai Pulin (Maxime's pharmacy (MaximPharmaceuticals)), Xi Wase (Civacir) (receiving) than biopharmaceutical company (Nabi Biopharmaceuticals Inc.), Intron A (Intron A)/Zadaxin (Zadaxin) (Lei Jin company (RegeneRx)), Levovirin (Li Ba drugmaker (Ribapharm Inc.)), Wei rummy pyridine (Li Ba drugmaker (Ribapharm Inc.)), He Puta enzyme (Heptazyme) (ribozyme pharmacy (Ribozyme Pharmaceuticals)), Intron A (Schering Plough (Schering-Plough)), PEG-Intron A (Schering Plough (Schering-Plough)), auspicious shellfish energy (Rebetron) (Schering Plough (Schering-Plough)), virazole (Schering Plough (Schering-Plough)), PEG-Intron A/virazole (Schering Plough (Schering-Plough)), Zha Dajimu (Zadazim) (match cloning companies (SciClone)), Rui Bifu (Rebif) (Xue Lannuo company (Serono)), IFN-β/EMZ701 (transition treatment company (TransitionTherapeutics)), T67 (Tularik Inc (Tularik Inc.)), VX-497 (Wei Taikesi drugmaker (VertexPharmaceuticals Inc.)), VX-950/LY-570310 (Wei Taikesi drugmaker (Vertex PharmaceuticalsInc.)), nurse Interferon, rabbit (Omniferon) (Wella Tianjin company (Viragen Inc.)) difficult to understand, XTL-002 (XTL bio-pharmaceuticals (XTL Biopharmaceuticals)), SCH 503034 (Schering Plough (Schering-Plough)), isatoribine (isatoribine) and its prodrug ANA971 and ANA975 (arna DIS (Anadys)), R1479 (Luo Shi bio-science (Roche Biosciences)), Wa Luopitabin (Valopicitabine) (Yi De Knicks company (Idenix)), NIM811 (Novartis Co.,Ltd (Novartis)) and Ai Ke are for grand (Actilon) (curry pharmacy (ColeyPharmaceuticals)).

In certain embodiments, the compositions and methods of the invention contain compound of the present invention and Interferon, rabbit.In certain aspects, Interferon, rabbit is selected from the group that is made up of following: interferon alpha 2B, polyoxyethylene glycol interferon alpha, Interferon alfacon-1, interferon alpha 2A and lymphoblastoid interferon-tau.

In other embodiments, the compositions and methods of the invention contain The compounds of this invention and are selected from the compound with anti-HCV activity by the following group that forms: interleukin II, interleukin 6, interleukin 12 (strengthening the compound of the development of 1 type helper cell reaction), RNA interfering, sense-rna, miaow Kui Mote (Imiqimod), virazole, inosine 5 '-single monophosphate dehydrogenase inhibitor, amantadine (amantadine) and Rimantadine (rimantadine).

In other embodiments, the compound with anti-HCV activity be that virazole, Levovirin, Wei Lami are fixed, thymosin, NS3 serpin and inosine list monophosphate dehydrogenase inhibitor, separately or the interferon-' alpha ' or the poly-second two glycol interferon-' alpha 's that make up surely with virazole or Wei Lami.

In another embodiment, the compound with anti-HCV activity is described HCV to be had active medicament, promptly separately or the interferon-' alpha ' or the polyoxyethylene glycol interferon-' alpha ' that make up surely with virazole or Wei Lami.

Example

In example hereinafter and the synthesis flow above, below abbreviation has following implication.If the foot couple abbreviation is defined, it has its common acceptable implication so.

μ L=microlitre

μ M=micro-molar concentration

μ g=microgram

NMR=nucleus magnetic resonance

Br=broad peak

D=doublet

δ=chemical shift

Dd=two group doublet

DMEM=Du Beikashi is modified according to Ge Shi substratum (Dulbeco ' s Modified Eagle ' s Medium)

DMF=N, dinethylformamide

DMSO=methyl-sulphoxide

DTT=dithiothreitol (DTT)

EDTA=ethylenediamine tetraacetic acid (EDTA)

ESI=electron spray ionisation

G=gram

H or hr=hour

HCV=hepatitis C virus

HPLC=high performance liquid chromatography

Hz=hertz

IPTG=sec.-propyl-β-D-thio-galactose pyran-glucoside

IU=international unit

IC ₅₀Inhibition concentration during=50% inhibition

J=coupling constant (unless otherwise mentioned, otherwise be unit with Hz)

M=multiplet

M=volumetric molar concentration

M+H ⁺=parent ion mass spectra peak adds H ⁺

Mg=milligram

ML=milliliter

MM=millimolar concentration

Mmol=mmole

MS=mass spectrum

Nm=nanometer

NM=nanomolar concentration

Ng=nanogram

NTA=nitrilotriacetic acid

NTP=nucleoside triphosphate

PCR=polymerase chain reaction

Ppm=PPM

Psi=pounds per square inch (p.p.s.i)

Rp-HPLC=RPLC

S=unimodal

T=triplet

TC ₅₀Toxic concentration during=50% cytotoxicity

Tetrakis or tetrakis=tetrakis triphenylphosphine palladium (O)

palladium

TFA=trifluoroacetic acid

THF=tetrahydrofuran (THF)

Tris=three (methylol) aminomethane

UTP=uridine triphosphate

Hereinafter set forth compound and the intermediate that is applicable to preparation compound of the present invention in the example.Be used to prepare these compounds synthetic schemes summary oneself in above setting forth.

Example 1

6-bromo-2-(4 '-chloro-4-methoxyl group-biphenyl-2-yl)-quinoline 4.11

Step 1.4-bromo-2-methyl isophthalic acid-nitro-benzene (4.2):

In ice-cold 10.0g (65.7mmol) 3-methyl-solution of 4-nitro-aniline in 200mL acetone, add 21mL (197.2mmol) 48% HBr.With 4.54g (65.7mmol) NaNO ₂Be dissolved in the 20mL water, and so that the speed that temperature remains on below 5 ℃ it is dropwise joined in the amine aqueous solution.The restir mixture is 10 minutes under this temperature, subsequently so that the speed that temperature remains on below 15 ℃ adds the solid-state CuBr of 1.5g (10mmol) by part.Do not finish (about 15 minutes) when having again to react when nitrogen is overflowed.Reaction mixture is evaporated to drying; Resistates is dissolved in the mixture of 500mL water and 750mL ethyl acetate.Separate organic phase, water (2 *), saturated NaCl (2 *) washing and dry (Na ₂SO ₄).Then it is evaporated to dry obtaining being the crude product of yellow solid shape, by filter in addition purifying via the 400mL silicagel pad of using the toluene elution;

Output: 10.45g (73%);

¹H-NMR(CDCl ₃)：δ(ppm)7.87(d，1H，J＝8.7Hz)，7.51-7.46(m，2H)，2.61(s，3H)。

Step 2.[(E)-2-(5-bromo-2-nitro-phenyl)-vinyl]-dimethyl-amine (4.4):

Under slow argon gas stream, under 145 ℃ (heating baths) with 9.26g (42.9mmol) compound 4.2,14.3mL (107.2mmol) N, the mixture heating up of dinethylformamide dimethylacetal 4.3 and 11 mL DMF 2 hours.Subsequently, reaction mixture is evaporated to drying.Leave standstill post crystallization and separate out dark pink product; MS:271.01 ﹠amp; 273.01 (M+H ⁺); ¹H-NMR (DMSO-d ₆): δ (ppm) 7.88 (d, 1H), 7.68 (dd, 1H), 7.58 (d, 1H), 7.05 (d, 1H), 5.59 (d, 1H), 2.90 (s, 6H).

Step 3.5-bromo-2-nitro-phenyl aldehyde (4.5):

(11.63g (42.9mmol)) is dissolved in the 1:1 mixture of 500mL THF and water with compound 4.4.In this solution, add 34.3g (160mmol) NaIO ₄, and at room temperature stirred the mixture 1 hour, dark-coloured solution becomes light yellow and follows a large amount of throw outs simultaneously.Leach solid matter, with 100mL ethyl acetate washed twice and compile organic phase and be evaporated to drying.Via the 400 mL silicagel pad filtration residue of using the toluene elution to obtain 7.08g (71%) title compound; ¹H-NMR (DMSO-d ₆): δ (ppm) 10.10 (s, 1H), 8.09-7.99 (m, 3H).

Step 4.2-amino-5-bromo-phenyl aldehyde (4.10):

Use L.I. Smith (L.I.Smith) and J.W. Europe send the program of (J.W.Opie) (organic synthesis book series (Org.Synth.Coll.) the 3rd volume, 56) by 5.45g (23.7mmol) compound 4.5 synthetic compounds 4.10, and productive rate is 55% (2.6g); MS:199.97 ﹠amp; 201.97 (M+H ⁺); ¹H-NMR (CDCl ₃): δ (ppm) 9.75 (s, 1H), 7.71 (s, 1H), 7.39 (d, 1H, J=9.3Hz), 7.22 (s, 2H), 6.72 (d, 1H, J=9.3Hz).

Step 5.1-(2-bromo-5-methoxyl group-phenyl)-ethyl ketone (4.8):

The 2M toluene solution that adds 9.63mL (19.25mmol) zinc methide in the solution of ice-cold 8.75g (35mmol) 2-bromo-5-methoxyl group-Benzoyl chloride in 40mL toluene is (because of the zinc methide spontaneous combustion, so should avoid contacting with air under argon atmospher! ).Remove ice bath and mixture slowly is warmed up to room temperature.Promptly carry out rapidly after the reaction beginning, produce turbid solution.Be reflected in 30 minutes and finish.Then, will react cooling and get back to 0 ℃ and by adding 10mL ethanol stopped reaction.Mixture is evaporated to drying, resistates is dissolved in the mixture of 50mL 1M HC1 and 100mL ethyl acetate.Separate organic phase, with 50mL water (2 *), salt solution (2 *) washing and dry (Na ₂SO ₄).The evaporation final solution, and in high vacuum dry oily matter whole night to obtain the title compound that 7.96g (99%) is the colourless liquid shape; ¹H-NMR (CDCl ₃): δ (ppm) 7.46 (d, 1H), 6.96 (d, 1H), 6.83 (dd, 1H), 3.80 (s, 3H), 2.63 (s, 3H).

Step 6.1-(4 '-chloro-4-methoxyl group-biphenyl-2-yl)-ethyl ketone (4.6):

Under argon gas, under 80 ℃ with compound 4.8 (6.0g, 26.19mmol), 4-chlorobenzene boric acid (4.51g, 28.81mmol) and Pd (PPh ₃) ₄(0.303g is 0.262mmol) in toluene (250mL), MeOH (60mL) and 2MNaHCO ₃Mixture (25mL) stirred 16 hours.After removing solvent, dried residue is dissolved in CHCl ₃Also filter (150mL).Evaporating solvent also passes through to use CHCl ₃-MeOH (70:1) as the chromatography purification resistates of scrub solution to obtain title compound (6.33g, 93%); ¹H NMR (CDCl ₃): 7.36 (d, 2H, J=8.4Hz), 7.27-7.21 (m, 4H), 7.02 (d, 1H, J=2.7Hz), 3.86 (s, 3H), 2.05 (s, 3H).MS(ESI)261.07(M+H)。

Step 7.6-bromo-2-(4 '-chloro-4-methoxyl group-biphenyl-2-yl)-quinoline (4.11):

Compound 4.11 (100mg (0.5mmol)) and compound 4.6 (130mg (0.5mmol)) are dissolved in the 5mL ethanol, add 800 μ L, 10% KOH (1.5mmol), and under argon gas, mixture remained in 90 ℃ of heating baths whole night.Evaporating solvent and water wet-milling resistates.400mL silicagel pad purifying semi-solid state compound 4.11 through using the toluene elution is to obtain the yellow viscous substance of 2.03g (44%); MS:424.03 ﹠amp; 426.03 (M+H ⁺); ¹H-NMR (DMSO-d ₆): δ (ppm) 8.20 (d, 1H, J=2.1Hz), 8.10 (d, 1H, J=9.0Hz), 7.93-7.83 (m, 2H), 7.40 (d, 1H, J=8.4Hz), 7.26-7.23 (m, 3H), 7.16-7.03 (m, 4H), 3.85 (s, 3H).

Example 2

Step 1.6-bromo-2-(2,4-dimethyl-thiazole-5-yl)-quinoline

To KOH (10.32 (85%) g, 156.27mmol) add in the solution in anhydrous EtOH (700mL) 2-amino-5-bromobenzaldehyde (10.42g, 52.09mmol) and 5-ethanoyl-2, the 4-dimethylthiazole (8.16mL, 60.42mmol).Under the 78C, under Ar, stirred the mixture 16 hours, and in ice bath, cool off subsequently.With 5NHCl it is neutralized to pH7 and is evaporated to about 60mL subsequently.Add entry (500mL).Collect formed throw out after filtration, water thorough washing and drying obtain 6-bromo-2-(2,4-dimethyl-thiazole-5-yl)-quinoline (15.62g, 94%).

Step 2.2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-boric acid

Under 90 ℃, under Ar with 6-bromo-2-(2,4-dimethyl-thiazole-5-yl)-quinoline (15g, 46.99mmol), two (neopentyl glycol foundation) two boron (31.83g, 141mmol), two (triphenylphosphine)-palladium (the II) (1.65g of chlorination, 2.35mmol) and potassium acetate (13.81g, 141mmol) mixture in anhydrous DMSO (260mL) stirred 2 hours, subsequently cool to room temperature.Mixture is poured in the water (1.2L) and, washed with water by filtering the collecting precipitation thing, and dry.In the solid of drying, add EtOAc (600mL) and leach insoluble solids.Evaporated filtrate and product is adsorbed on the silica gel, and obtain 2-(2 through short silicon-dioxide pad purifying with EtOAc-hexane (5:2) elution, 4-dimethyl-thiazole-5-yl)-quinoline-6-boric acid (16.4g, NMR show still contain 30% pair of (neopentyl glycol foundation) two boron of having an appointment, productive rate is 94%).Example 3

2-(2,4-dimethyl-thiazole-5-yl)-8-fluoro-quinoline-6-boric acid

Step 1.4-amino-3-fluoro-boric acid

Under fluorine gas, under 60 ℃ with commercially available 4-bromo-2-fluoroaniline (500mg, 2.6mmol), potassium acetate (764mg, 7.8mmol), [P (Ph ₃)] ₂Pd (II) Cl ₂(18mg, 0.026mmol) (1.76g, 7.8mmol) mixture heating up in 13mL DMSO whole night with two (neopentyl glycol foundation) two boron.Reaction mixture is diluted water and salt water washing, drying (sodium sulfate) and concentrated with ethyl acetate.Use RP-HPLC purifying crude product to obtain 4-amino-3-fluoro-boric acid.

Step 2.4-amino-3-fluoro-5-iodo-boric acid

The N-iodosuccinimide that is used for acetate is handled 4-amino-3-fluoro-boric acid.Reaction mixture is diluted water and salt water washing, dry (sodium sulfate) and the concentrated 4-amino-3-fluoro-5-iodo-boric acid that obtains with ethyl acetate.

Step 3.4-amino-3-fluoro-5-formyl radical-boric acid

4-amino-3-fluoro-5-iodo-boric acid is dissolved among the THF, simultaneously CO is blasted reaction vessel.Add four (triphenylphosphinyl) palladiums and reaction is heated to 50 ℃.Add tributyltin hydride.Reaction mixture is diluted with ethyl acetate, water and salt water washing, dry (sodium sulfate) concentrates and purifying obtains 4-amino-3-fluoro-5-formyl radical-boric acid.

Step 4.2-(2,4-dimethyl-thiazole-5-yl)-8-fluoro-quinoline-6-boric acid

Make compound 4-amino-3-fluoro-5-formyl radical-boric acid, 5-ethanoyl-2,4-dimethylthiazole and the 10%KOH/ ethanol mixture in ethanol refluxes whole night.Reactant is concentrated, and water wet-milling and purifying obtain 2-(2,4-dimethyl-thiazole-5-yl)-8-fluoro-quinoline-6-boric acid.

Example 4

5-(2-chloro-quinoline-6-yl)-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (7.8)

Step 1.5-methyl 4-nitro-thiophene-2-carboxylic acid (7.2)

In dry ice/acetone batch, diacetyl oxide (17mL, 176mmol, 5 equivalents) is cooled to-78 ℃, and slowly adds nitrosonitric acid (6mL, 113mmol, 3.2 equivalents), and mixture is warmed up to-20 ℃.Slowly add 5-methyl-thiophene-2-carboxylic acid 7.1 (5g, 35.2mmol, 1 equivalent) (heat release rapidly) with aliquot.Temperature-20 ℃ and+10 ℃ between the fluctuation, be stabilized in-20 ℃ subsequently.-20 ℃ of following stirred reaction mixtures 10 minutes.Obtain throw out with frozen water stopped reaction mixture subsequently, collect described throw out after filtration and wash with frozen water.From EtOH/H ₂O recrystallize pink solid.Crystals collected is washed dry air and dry in a vacuum to obtain being the 5-methyl-4-nitro-thiophene-2-carboxylic acid 7.2 (3.24g, 50%) of pink-brown solid shape with frozen water.Scale reaction repeated (output 9.82g, 50%) with 15 grams.MS：188.70(M+H ⁺)； ¹H-NMR(DMSO-d ₆)：δ(ppm)13.77(bs，1H)，8.00(s，1H)，2.79(s，3H)。

Step 2.5-methyl 4-nitro-thiophene-2-carboxylic acid methyl esters (7.3)

Handle the compound 7.2 (10g, 53.4mmol, 1 equivalent) in MeOH (100mL) and be heated to reflux with sulfuric acid (10mL, 19mmol, 3.5 equivalents) and reach 1 day.After reaction mixture is cooled to envrionment temperature, evaporating solvent.Resistates is dissolved among the EtOAc and uses saturated NaHCO ₃End, separate each layer subsequently.With organic layer with the salt water washing, dry (Na ₂SO ₄), filter, concentrate and dry in a vacuum 5-methyl-4-nitro-thiophene-2-carboxylic acid methyl esters 7.3 (9.95g, 93%) to obtain being light brown solid state.MS：202.00(M+H ⁺)； ¹H-NMR(DMSO-d ₆)：δ(ppm)8.06(s，1H)，3.84(s，3H)，2.78(s，3H)。

Step 3.2-chloro-6-brooethyl-quinoline and 2-chloro-6-two brooethyls-quinoline (7.5)

Under argon gas, in the solution of 2-chloro-6-toluquinoline 7.4 (2g, 11.3mmol, 1 equivalent) in benzene (13mL), add NBS (4g, 23mmol, 2 equivalents), add benzoyl peroxide (0.365g, 1.13mmol, 0.10 equivalent) subsequently.Mixture heating up is reached 4 hours to refluxing.Behind the cool to room temperature, evaporating solvent and resistates is dissolved among the DCM and uses saturated NaHCO ₃Washing.With organic layer drying (Na ₂SO ₄), filter and concentrate.By ISCO (DCM:Hex=4:1) purifying crude product obtain being white in color the 2-chloro-6-brooethyl-quinoline and the 2-chloro-6-two brooethyls-quinoline 7.5 (3g of solid state, 80%), judge that according to HPLC described solid is by single bromo-quinoline of 1:8 ratio: two bromo-quinoline are formed.TLC gradient DCM:Hex=4:1.2-chloro-6-brooethyl-quinoline: MS:255.65 ﹠amp; 257.65 (M+H ⁺); 2-chloro-6-two brooethyls-quinoline: MS:333.80; 335.80 ﹠amp; 337.80 (M+H ⁺).

Step 4.2-chloro-quinoline-6-formaldehyde (7.6)

The 1:8 mixture of bromination quinoline 7.5 (3g, 9.24mmol, 1 equivalent) and vulkacit H (3.89g, 28mmol, 3 equivalents) is heated to reflux in 50% aqueous ethanolic solution (16mL) reaches 1 hour.Behind the cool to room temperature, add entry (10mL), with after slowly added 12N HCl (1.50mL) in 5 minutes.Reaction mixture is heated to backflow reaches 0.5 hour, subsequently cool to room temperature.Reaction mixture joined in the salt solution and with DCM extraction 4 times.With collected organism with salt water washing 2 times, dry (Na ₂SO ₄), filter and concentrate.The drying solid 2-chloro-quinoline-6-formaldehyde 7.6 (1.63g, 92%) of solid state that obtains being white in color in a vacuum, it is used without being further purified promptly.MS:192.00 (M+H ⁺); ¹H-NMR (DMSO-d ₆): δ (ppm) 10.17 (s, 1H), 8.69 (m, 1H), 8.68 (d, 1H, J=8.4Hz), and 8.21 (dd, 1H, J=9.0Hz and 1.8Hz), 8.09 (dd, 1H, J=8.4Hz and 0.60Hz), 7.75 (d, 1H, J=8.4Hz).

Step 5.5-[(E)-2-(2-chloro-quinoline-6-yl)-vinyl]-4-nitro-thiophene-2-carboxylic acid methyl esters (7.7)

Handle the solution of compound 7.3 (1.71g, 8.51mmol, 1 equivalent) in MeOH (35mL) with compound 7.6 (1.63g, 8.51mmol, 1 equivalent).Reaction mixture is heated to backflow up to obtaining solution.The tetramethyleneimine (70 μ L, 0.0605g, 0.851mmol, 0.10 equivalent) that adds catalytic amount subsequently.Reaction mixture is heated to backflow whole night.Behind the cool to room temperature, evaporating solvent obtains resistates, by ISCO (gradient Hex:EtOAc=100:0 to 0:100) in addition purifying obtain being the 5-[(E of orange red solid state)-2-(2-chloro-quinoline-6-yl)-vinyl]-4-nitro-thiophene-2-carboxylic acid methyl esters 7.7 (2.62g, 82%).TLC gradient Hex:EtOAc=1:1.MS：375.70(M+H ⁺)； ¹H-NMR(DMSO-d ₆)：δ(ppm)8.50(d，1H，J＝8.7Hz)，834(bs，1H)，8.18(m，1H)，8.16(bs，1H)，8.00(d，1H，J＝9.0Hz)，7.80(d，1H，J＝16.5Hz)，7.65(d，1H，J＝8.7Hz)，7.30(d，1H，J＝17.4Hz)，3.89(s，3H)。

Step 6.5-(2-chloro-quinoline-6-yl)-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (7.8)

The solution of compound 7.7 (2.62g, 7.00mmol, 1 equivalent) in triethyl-phosphite (7mL) is heated to backflow (160 ℃) reaches 2 hours.Behind the cool to room temperature, [the P (OEt) of evaporating solvent under high vacuum ₃Boiling point is 153-157 ℃; OP (OEt) ₃Boiling point is 215 ℃], water-bath is maintained 70 ℃ simultaneously.Resistates is dissolved among the EtOAc and with normal hexane precipitates.Solid is collected after filtration and washed with the 5%EtOAc/ normal hexane.Behind the dry air number minute, drying solid obtains being the target compound 7.8 (960mg, 40%) of tawny solid state in a vacuum.TLC gradient Hex:EtOAc=1:1.MS：343.00(M+H ⁺)； ¹H-NMR(DMSO-d ₆)：δ(ppm)12.3(bs，1H)，8.39(m，2H)，8.24(d，1H，J＝8.7Hz)，8.00(d，1H，J＝8.7Hz)，7.71(s，1H)，7.61(d，1H，J＝9.0Hz)，7.16(s，1H)，3.82(s，3H)。

Example 5

6-hexamethylene-1-thiazolinyl-5-[2-(2-fluoro-phenyl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 186)

Step 1.5-[2-(2-fluoro-phenyl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (8.2a)

With 387mg (1.13mmol) compound 7.8 (example 4), 237mg (1.69mmol, 1.5 equivalents) 2-fluorophenyl boric acid and 65mg (0.057mmol, 0.05 equivalent) Pd (PPh ₃) ₄The microwave reaction container of packing into.To wherein adding 12mL dioxan and 4mL 1M K ₃PO ₄The aqueous solution.Sealed reaction vessel, and make its degassing subsequently and purify 2 times with Ar.With microwave reaction mixture is heated to 120 ℃ subsequently and reaches 10 minutes.HPLC analyzes and confirms compound 7.8 completely consumed.Make the reaction mixture cool to room temperature, form throw out during this period.Throw out is collected after filtration, used cold H ₂O washing and under vacuum drying obtain 5-[2-(2-fluoro-phenyl)-quinoline-6-yl that 399mg (88%) is the yellow powder shape]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate 8.2a.MS：403.1(M+H ⁺)。

Step 2.6-hexamethylene-1-thiazolinyl-5-[2-(2-fluoro-phenyl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (8.3a)

With 245mg (0.61mmol) compound 8.2a, 947 μ L (9.15mmol, 15 equivalents) pimelinketone, 500 μ L diacetyl oxides, 500 μ L 85%H ₃PO ₄With the 4mL acetate microwave reaction container of packing into.Sealed reaction vessel and be heated 180 ℃ with microwave and reach 75 minutes.HPLC analyzes and confirms compound 8.2a completely consumed.Under 0 ℃, pour reaction mixture into 50mL NH ₄Among the OH (concentrated aqueous solutions).Use H again ₂O dilution aqueous mixture and with ethyl acetate extraction 3 times.Use HCl (1M, the aqueous solution), NaHCO subsequently ₃The extract that (saturated aqueous solution) and salt water washing have merged.Then with organic phase through Na ₂SO ₄Drying is filtered and concentrated 6-hexamethylene-1-thiazolinyl-5-[2-(the 2-fluoro-phenyl)-quinoline-6-yl that obtains]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate 8.3a.The thick resistates of vacuum-drying and its are used without being further purified promptly.MS：483.1(M+H ⁺)。

Step 3.6-hexamethylene-1-thiazolinyl-5-[2-(2-fluoro-phenyl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 186)

With pack into reaction vessel and dissolve of 75mg (0.16mmol) compound 8.3a with 8mL DMF.Add 11mg (0.31mmol, 2 equivalents) NaH (67% in mineral oil) and stirred reaction mixture at room temperature subsequently.After 15 minutes, disposable adding 36 μ L (0.31mmol, 2 equivalents) 2-chloro-1-morpholine-4-base-ethyl ketone and at room temperature lasting stirred reaction mixture.After 3 hours, HPLC and LC-MS analyze and confirm compound 8.3a completely consumed.By adding 0.1mL H ₂O stopped reaction mixture is poured in the 50mL flask and concentrates.Then with cold H ₂O joins in the thick resistates and is dark pulverous methyl esters with precipitation.By centrifugal collection solid and use H ₂O washs once more.Subsequently, methyl esters is transferred in the reaction flask and with 3mL THF, 1mL MeOH and 1mL LiOH (1M, the aqueous solution) dissolving.Subsequently, reaction mixture is heated to 50 ℃ and analyze careful monitoring by HPLC and LC-MS.After conversion was finished, usefulness 0.5mL HCl (2M, the aqueous solution) neutralization reaction mixture also concentrated.Subsequently with thick resistates with DMF dissolving and use the TFA acidifying.Then filtering mixt and obtain 6-hexamethylene-1-thiazolinyl-5-[2-(2-fluoro-phenyl)-quinoline-6-yl that 35mg (37%) is the orange powder shape by the reversed-phase HPLC purifying]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 186).MS：596.2(M+H ⁺)； ¹H?NMR(DMSO-d6)：δ(ppm)8.55(d，J＝8.1，1H)，8.17(d，J＝8.7，1H)，8.09(td，J＝7.9，1.7，1H)，8.03-7.99(m，2H)，7.91(s，1H)，7.73(dd，J＝8.4，1.7，1H)，7.65-7.58(m，1H)，7.48-7.41(m，2H)，5.81-5.78(m，1H)，5.00(s，2H)，3.48-3.33(m，8H)，2.12(br?s，2H)，1.99(br?s，2H)，1.54(br?s，4H)。

Example 6

6-hexamethylene-1-thiazolinyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 187)

Step 1.5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (8.2b)

With 500mg (1.46mmol) compound 7.8 (example 4), 436mg (1.82mmol, 1.25 equivalents) 2,4-dimethyl-thiazole-5-boric acid pinacol ester and 84mg (0.073mmol, 0.05 equivalent) Pd (PPh ₃) ₄The microwave reaction container of packing into.To wherein adding 12mL dioxan and 4mL K ₃PO ₄(1M, the aqueous solution).Sealed reaction vessel, and make its degassing subsequently and purify 2 times with Ar.Subsequently, with microwave reaction mixture is heated to 120 ℃ and reaches 10 minutes.HPLC analyzes and confirms compound 7.8 completely consumed.Make the reaction mixture cool to room temperature, form throw out during this period.Throw out by centrifugal collection, is used cold H ₂O washing and under vacuum drying obtain 5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl that 506mg (81%) is the yellow powder shape]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate 8.2b.MS：420.1(M+H ⁺)。

Step 2.6-hexamethylene-1-thiazolinyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (8.3b)

With 200mg (0.48mmol) compound 8.2b, 740 μ L (7.16mmol, 15 equivalents) pimelinketone, 400 μ L diacetyl oxides, 400 μ L 85%H ₃PO ₄With the 4mL acetate microwave reaction container of packing into.Sealed reaction vessel and be heated 150 ℃ with microwave and reach 100 minutes.HPLC analyzes and confirms the own completely consumed of compound 8.2b.Under 0 ℃, pour reaction mixture into 50mL NH ₄Among the OH (concentrated aqueous solutions).Use H again ₂O dilution aqueous mixture and with ethyl acetate extraction 3 times.Use HCl (1M, the aqueous solution), NaHCO subsequently ₃The extract that (saturated aqueous solution) and salt water washing have merged.Then with organic phase through Na ₂SO ₄Drying is filtered and concentrated 6-hexamethylene-1-thiazolinyl-5-[2-(2, the 4-dimethyl-thiazole-5-yl)-quinoline-6-yl that obtains]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate 8.3b.The thick resistates of vacuum-drying and its are used without being further purified promptly.MS：500.1(M+H ⁺)。

Step 3.6-hexamethylene-1-thiazolinyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 187)

With pack into reaction vessel and dissolve of 56mg (0.11mmol) compound 8.3b with 4mL DMF.Add 9mg (0.22mmol, 2 equivalents) NaH (60% in mineral oil) and stirred reaction mixture at room temperature subsequently.After 15 minutes, disposable adding 26 μ L (0.22mmol, 2 equivalents) 2-chloro-1-morpholine-4-base-ethyl ketone and at room temperature lasting stirred reaction mixture.After 6 hours, HPLC and LC-MS analyze and confirm compound 8.3b completely consumed.By adding 0.1mL H ₂O stopped reaction mixture is poured in the 50mL flask and concentrates.Then with cold H ₂O joins in the thick resistates and is dark pulverous methyl esters with precipitation.By centrifugal collection solid and use H ₂O washs once more.Subsequently, methyl esters is transferred in the reaction flask and with 3mL THF, 1mL MeOH and 1mL LiOH (1M, the aqueous solution) dissolving.Subsequently, reaction mixture is heated to 50 ℃ and analyze careful monitoring by HPLC and LC-MS.After conversion was finished, usefulness 0.5mL HCl (2M, the aqueous solution) neutralization reaction mixture also concentrated.Subsequently with thick resistates with DMF dissolving and use the TFA acidifying.Obtain 6-hexamethylene-1-thiazolinyl-5-[2-(2 that 15mg (22%) is the orange powder shape with the mixture filtration and by the reversed-phase HPLC purifying then, 4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 187).MS：613.2(M+H ⁺)； ¹H?NMR(DMSO-d6)：δ(ppm)8.51(d，J＝8.7，1H)，8.04(d，J＝8.7，1H)，7.97-7.90(m，3H)，7.68(dd，J＝8.7，2.0，1H)，5.78(br?s，1H)，4.99(s，2H)，3.46-3.32(m，8H)，2.76(s，3H)，2.71(s，3H)，2.11(br?s，2H)，1.97(br?s，2H)，1.53(br?s，4H)。

Example 7

6-cyclohexyl-5-[2-(2-fluoro-phenyl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 188)

Step 1.6-cyclohexyl-5-[2-(2-fluoro-phenyl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (8.4a)

With 235mg (0.49mmol) compound 8.3a (example 5, step 2), 116 μ L (0.73mmol, 1.5 equivalents) triethyl silicane and the 5mL TFA microwave reaction container of packing into.Sealed reaction vessel and be heated 70 ℃ with microwave and reach 5 minutes.LC-MS analyzes and confirms compound 8.3a completely consumed.Pour among the 50mL reaction mixture and concentrated pulverous 6-cyclohexyl-5-[2-(the 2-fluoro-phenyl)-quinoline-6-yl that obtains taking on a red color]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate 8.4a.The thick resistates of vacuum-drying and its are used without being further purified promptly.MS：485.1(M+H ⁺)。

Step 2.6-cyclohexyl-5-[2-(2-fluoro-phenyl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 188)

With pack into reaction vessel and dissolve of 307mg (0.63mmol) compound 8.4a with 20mL DMF.Add 50mg (1.26mmol, 2 equivalents) NaH (60% in mineral oil) and stirred reaction mixture at room temperature subsequently.After 15 minutes, disposable adding 146 μ L (1.26mmol, 2 equivalents) 2-chloro-1-morpholine-4-base-ethyl ketone and at room temperature lasting stirred reaction mixture.After 75 minutes, HPLC and LC-MS analyze and confirm the own completely consumed of compound 8.4a.By adding 0.5mL H ₂O stopped reaction mixture is poured in the 50mL flask and concentrates.Then with cold H ₂O joins in the thick resistates and is dark pulverous methyl esters with precipitation.By centrifugal collection solid and use H ₂O washs once more.Subsequently, methyl esters is transferred in the reaction flask and with 6mL THF, 2mL MeOH and 2mL LiOH (1M, the aqueous solution) dissolving.Subsequently, reaction mixture is heated to 50 ℃ and analyze careful monitoring by HPLC and LC-MS.After conversion was finished, usefulness 1mL HCl (2M, the aqueous solution) neutralization reaction mixture also concentrated.Subsequently with thick resistates with DMF dissolving and use the TFA acidifying.Obtain 6-cyclohexyl-5-[2-(2-fluoro-phenyl)-quinoline-6-yl that 107mg (28%) is the orange powder shape with the mixture filtration and by the reversed-phase HPLC purifying then]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 188).MS：598.2(M+H ⁺)； ¹H?NMR(DMSO-d6)：δ(ppm)8.58(d，J＝8.3，1H)，8.22(d，J＝8.6，1H)，8.11-7.99(m，3H)，7.86(s，1H)，7.73(dd，J＝8.6，2.0，1H)，7.65-7.58(m，1H)，7.48-7.42(m，2H)，5.01(s，2H)，3.51-3.37(m，8H)，2.59(m，1H)，2.53-1.25(m，10H)。

Example 8

6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 189)

Step 1.6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (8.4b)

With 360mg (0.72mmol) compound 8.3b (example 6, step 2), 172 μ L (1.08mmol, 1.5 equivalents) triethyl silicane and the 7mL TFA 100mL round-bottomed flask of packing into.Reaction mixture was covered and at room temperature stirs 1 hour.LC-MS analyzes and confirms compound 8.3b completely consumed.Concentrated reaction mixture obtains 6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate 8.4b.The thick resistates of vacuum-drying and its are used without being further purified promptly.MS：502.1(M+H ⁺)。

Step 2.6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 189)

With pack into reaction vessel and dissolve of 361mg (0.72mmol) compound 8.4b with 20mL DMF.Add 58mg (1.44mmol, 2 equivalents) NaH (60% in mineral oil) and stirred reaction mixture at room temperature subsequently.After 15 minutes, disposable adding 167 μ L (1.44mmol, 2 equivalents) 2-chloro-1-morpholine-4-base-ethyl ketone and at room temperature lasting stirred reaction mixture.After 60 minutes, HPLC and LC-MS analyze and confirm the own completely consumed of compound 8.4b.By adding 0.5mL H ₂O stopped reaction mixture is poured in the 50mL flask and concentrates.Then with cold H ₂O joins in the thick resistates and is dark pulverous methyl esters with precipitation.By centrifugal collection solid and use H ₂O washs once more.Subsequently, methyl esters is transferred in the reaction flask and with 6mL THF, 2mL MeOH and 2mL LiOH (1M, the aqueous solution) dissolving.Subsequently, reaction mixture is heated to 50 ℃ and analyze careful monitoring by HPLC and LC-MS.After conversion was finished, usefulness 1mL HCl (2M, the aqueous solution) neutralization reaction mixture also concentrated.Subsequently with thick resistates with DMF dissolving and use the TFA acidifying.Obtain 6-cyclohexyl-5-[2-(2 that 178mg (39%) is the orange powder shape with the mixture filtration and by the reversed-phase HPLC purifying then, 4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-morpholine-4-base-2-oxo-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 189).MS：615.2(M+H ⁺)； ¹HNMR(DMSO-d6)：δ(ppm)8.53(d，J＝8.3，1H)，8.08(d，J＝8.6，1H)，7.96-7.93(m，2H)，7.86(s，1H)，7.68(dd，J＝8.6，1.8，1H)，5.00(s，2H)，3.51-3.36(m，8H)，2.76(s，3H)，2.71(s，3H)，1.86-1.20(m，10H)。

Example 9

6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-oxo-2-thiomorpholine-4-base-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 44 and compound 190)

Step 1.4-tertiary butyloxycarbonyl ylmethyl-6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (9.1)

With 191mg (0.38mmol) compound 8.4b (pack into reaction vessel and dissolve of example 8, step 1) with 15mL DMF.Add 30mg (0.76mmol, 2 equivalents) NaH (60% in mineral oil) and stirred reaction mixture at room temperature subsequently.After 15 minutes, disposable adding 112 μ L (0.76mmol, 2 equivalents) the bromoacetic acid 2-tert-butyl ester and at room temperature lasting stirred reaction mixture.Analyze monitoring reaction by HPLC and LC-MS.After compound 8.4b transforms and finishes, by adding 0.5mL H ₂O stopped reaction mixture is poured in the 50mL flask and concentrates.Then with cold H ₂O joins in the thick resistates and is dark pulverous methyl esters with precipitation.By centrifugal collection solid and use H ₂O washs once more.Dry 4-tertiary butyloxycarbonyl ylmethyl-6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl under vacuum then]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate 9.1 crude products and its used without being further purified promptly.MS：616.1(M+H ⁺)。

Step 2.4-carboxymethyl-6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate (9.2)

234mg (0.38mmol) compound 9.1 packed in the 50mL flask and with the 4MHCl dissolving of 5mL in dioxan.Add 250 μ L (5%v/v) methyl-phenoxides and stirred reaction mixture at room temperature subsequently.After HPLC and LC-MS analysis revealed compound 9.1 transform fully, concentrated reaction mixture.Dry 4-carboxymethyl-6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl under vacuum simply then]-4H-thieno-[3,2-b] pyrroles-2-methyl-formiate 9.2 crude products and its used without being further purified promptly.MS：560.1(M+H ⁺)。

Step 3.6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-oxo-2-thiomorpholine-4-base-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 190)

With pack into reaction vessel and dissolve of 107mg (0.19mmol) compound 9.2 with 3mL DMF.Add 86mg (0.23mmol, 1.2 equivalents) HBTU and 73 μ L (0.42mmol, 2.2 equivalents) DIEA and stirred reaction mixture at room temperature subsequently.After 15 minutes, disposable adding 24 μ L (0.24mmol, 1.25 equivalents) thiomorpholine and lasting stirred reaction mixture under 35 ℃.HPLC and LC-MS analyze confirm that compound 9.2 transforms fully after, by the fast vacuum concentrated reaction mixture.Then with cold H ₂O joins in the thick resistates with the precipitation methyl esters.By centrifugal collection solid and use H ₂O washs once more.Subsequently, methyl esters is transferred in the reaction flask and with 3mL THF, 1mLMeOH and 1mL LiOH (1M, the aqueous solution) dissolving.Subsequently, reaction mixture is heated to 50 ℃ and analyze careful monitoring by HPLC and LC-MS.After conversion was finished, usefulness 0.5mL HCl (2M, the aqueous solution) neutralization reaction mixture also concentrated.Subsequently with thick resistates with DMF dissolving and use the TFA acidifying.Obtain 6-cyclohexyl-5-[2-(2 that 24mg (20%) is the orange powder shape with the mixture filtration and by the reversed-phase HPLC purifying then, 4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-oxo-2-thiomorpholine-4-base-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 190).MS：631.2(M+H ⁺)； ¹H?NMR(DMSO-d6)：δ(ppm)8.53(d，J＝8.8，1H)，8.08(d，J＝8.8，1H)，7.95-7.87(m，3H)，7.68(dd，J＝8.5，2.0，1H)，5.00(s，2H)，3.67-3.57(m，4H)，2.76(s，3H)，2.71(s，3H)，2.47-2.35(m，4H)，1.86-1.21(m，10H)。

Example 10

6-cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-oxo-2-piperidines-1-base-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 35 and compound 191)

With pack into reaction vessel and dissolve of 107mg (0.19mmol) compound 9.2 (example 9, step 2) with 3mL DMF.Add 86mg (0.23mmol, 1.2 equivalents) HBTU and 73 μ L (0.42mmol, 2.2 equivalents) DIEA and stirred reaction mixture at room temperature subsequently.After 15 minutes, disposable adding 24 μ L (0.24mmol, 1.25 equivalents) piperidines and lasting stirred reaction mixture under 35 ℃.HPLC and LC-MS analyze confirm that compound 9.2 transforms fully after, by the fast vacuum concentrated reaction mixture.Then with cold H ₂O joins in the thick resistates with the precipitation methyl esters.By centrifugal collection solid and use H ₂O washs once more.Subsequently, methyl esters is transferred in the reaction flask and with 3mLTHF, 1mL MeOH and 1mL LiOH (1M, the aqueous solution) dissolving.Subsequently, reaction mixture is heated to 50 ℃ and analyze careful monitoring by HPLC and LC-MS.After conversion was finished, usefulness 0.5mL HCl (2M, the aqueous solution) neutralization reaction mixture also concentrated.Subsequently with thick resistates with DMF dissolving and use the TFA acidifying.Obtain 6-cyclohexyl-5-[2-(2 that 24mg (21%) is the orange powder shape with the mixture filtration and by the reversed-phase HPLC purifying then, 4-dimethyl-thiazole-5-yl)-quinoline-6-yl]-4-(2-oxo-2-piperidines-1-base-ethyl)-4H-thieno-[3,2-b] pyrroles-2-formic acid (compound 191).MS：613.2(M+H ⁺)； ¹H?NMR(DMSO-d6)：δ(ppm)8.52(d，J＝8.5，1H)，8.07(d，J＝8.5，1H)，7.95-7.92(m，2H)，7.82(s，1H)，7.69(d，J＝8.2，1H)，5.96(s，2H)，3.38-3.26(m，4H)，2.76(s，3H)，2.71(s，3H)，1.86-1.24(m，16H)。

Indication compound 1-34,36-43 in the Table I and 45-185 can be prepared like universal synthesis method and above-mentioned example class.

Biological example

Biological example 1. hepatitis C resistant activity

Compound can be by suppressing the HCV polysaccharase, representing the hepatitis C resistant activity by other required in inhibition replication cycle enzyme or by other path.Disclose multiple in order to assess these active calibratings.Disclose the overall universal method that increases of HCV virus in the assessment culture in No. the 5th, 738,985, Myers people's such as (Miles) the United States Patent (USP).Ferrari people such as (Ferrari), viral magazine (Jnl.of Vir :), 73:1649-1654,1999; Shi Jing people such as (Ishii), hepatology (Hepatology), 29:1227-1235,1999; Luo Man people such as (Lohmann), biochemical magazine (Jnl.of Bio.Chem.), 274:10807-10815,1999; With people such as (Yamashita) under the mountain, biochemical magazine (Jnl.of Bio.Chem.), 273:15479-15486, oneself reports in vitro checking method in 1998.

Emory University (Emory University) on September 27th, 1996 apply for (list C. Hagedorn (C.Hagedorn) with A. Reynolds Du Si (A.Reinoldus) as the inventor) and the WO 97/12033 of the right of priority of No. the 60/004th, 383, the U.S. Provisional Patent Application case of advocating to be applied for September nineteen ninety-five in the active HCV polysaccharase checking method that can be used for assessing compound described herein has been described.Ba Suoluo maze people such as (Bartholomeusz), " using hepatitis C virus (HCV) the RNA polymerase checking method of clone HCV nonstructural proteins " (Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins); Reported another kind of HCV polysaccharase checking method among antiviral therapy (Antiviral Therapy) 1996:1 (the increasing version 4) 18-24.

Kai Zi people's such as (Katze) No. the 6th, 030,785, United States Patent (USP), the United States Patent (USP) the 6th of Delvecchio (Delvecchio), 228, No. 576 and bring up to have disclosed in refined (Jubin) people's of etc.ing the United States Patent (USP) the 5th, 759,795 and measure because the sieve method of the drug induced kinase activity reduction of HCV.The people's such as (Su) of Soviet Union United States Patent (USP) the 5th, 861, No. 267, moral Francisco people's such as (De Francesco) United States Patent (USP) the 5th, 739, No. 002 and the people's such as (Houghton) that pauses suddenly United States Patent (USP) the 5th, the sieve method of the protease inhibiting activity of the HCV medicine that has disclosed measurement in 597, No. 691 and proposed.

The calibrating of biological example 2. replicons

Use clone ET (Huh-lucubineo-ET) screening to be used to suppress the compound of HCV RNA RNA-dependent polysaccharase.With containing 1 ₃₈₉The rna transcription thing stable transfection ET clone (Ke Laige people such as (Krieger), 2001 and unexposed) of luc-ubi-neo/NS3-3 '/ET (having Photinus pyralis LUC-ubiquitin-neomycin phosphotransferase fusion rotein and the replicon that contains the driving NS3-5B polymeric protein of EMCV-IRES of cell culture adaptive mutation (E1202G, T1280I, K1846T)).The ET cell is grown in be supplemented with 10% foetal calf serum, 2mM glutamine, penicillin (Penicillin) (100IU/mL)/DMEM of Streptomycin sulphate (100 μ g/mL), 1 * non-essential amino acid and 250 μ g/mL G418 (" Geneticin (Geneticin) ") in.It is all available from Life Technologies, Inc. (LifeTechnologies) (Bai Saisida city (Bethesda), the Maryland State (MD)).With every hole 0.5-1.0 * 10 ⁴Individual cell in 96 orifice plates and cultivated 24 hours, adds test compounds with cell inoculation subsequently.Compound is joined in the cell with the ultimate density of acquisition 0.1nM to 50 μ m and 0.5% final DMSO concentration.(catalog number (Cat.No.) Glo-dissolves damping fluid E2661 and the Bright-Glo luciferase E2620 of system by adding dissolving damping fluid and substrate after 48-72 hour, Pu Luomaige company (Promega), Madison city (Madison), Wisconsin State (WI)) measure uciferase activity.Cell should too not merge during the calibrating.Drafting is with respect to the inhibition chart of percentage comparison of the copy data of no compound contrast.Under the same conditions, use cell proliferation reagent WST-1 (Luo Shi (Roche), Germany (Germany)) to measure the cytotoxicity of compound.Selection is showed antiviral activity but is not had remarkable Cytotoxic compound to determine EC ₅₀And TC ₅₀, it is effective concentration and the toxic concentration of observing under 50% maximum the inhibition.Measure with regard to these, each compound is used 10 points, 2 times of serial dilutions, this crosses over 1000 times concentration range.By the inhibition % match under each concentration is calculated EC to following equation ₅₀Value and calculate TC similarly ₅₀Value:

Suppress %=100%/[(EC ₅₀/ [I]) ^b+ 1],

Wherein b is hill coefficient (Hill ' s coefficient).

In certain aspects, when testing according to the checking method of example 2, formula (I) compound will have the EC that is equal to or less than 50 μ M ₅₀In others, EC ₅₀Be equal to or less than 10 μ M.In others, EC ₅₀Be equal to or less than 5 μ M.

When under 6.25 μ M, testing, find that respectively compound 186-191 has following inhibition % value: 75,63,99,100,98 and 97.

The cloning and expression of biological example 3. recombinant HCVs-NS5b

As Luo Man .V. (Lohmann V.) waits people (1999) science (Science) 285, and 110-113 is described, use be showed in the 266th page of WO 2005/012288 primer by PCR from pFKI ₃₈₉Luc/NS3-3 '/proteic the encoding sequence of ET clone NS5b.

21 amino-acid residues of the fragment deletion C-terminal of being cloned.The fragment of being cloned is inserted in proteinic C-terminal place to be provided in the IPTG inducible expression plasmid of epitope tag (His) 6.

Express recombinant enzyme in the XL-1 cell, and after abduction delivering, use affinity chromatography protein purification on nickel-NTA post.Condition of storage is under-20 ℃, 10mM Tris-HCl (pH7.5), 50mM NaCl, 0.1mM EDTA, 1mM DTT, 20% glycerine.

The calibrating of biological example 4.HCV-NS5b enzyme

Examine and determine polymerase activity through radiolabeled UTP by measure using to incorporate in the RNA product through biotinylated assorted poly-template (it comprises a part of HCV genome).Calibrating mixture (50 μ L) contains 10mMTris-HCl (pH7.5), 5mM MgCl usually ₂, 0.2mM EDTA, 10mM KCl, 1 unit/microlitre RNAsin, 1mM DTT, the various NTP of 10 μ M (comprise [ ³H]-UTP) and the assorted poly-template of 10ng/ μ L.Initial test compounds is dissolved among 100% DMSO and further diluted in the aqueous buffer solution that contains 5% DMSO.Usually test compounds under the concentration between 1nM and the 100 μ M.Reaction is initial and make and be reflected at 37 ℃ and continue 2 hours down to add enzyme.With 8 μ L 100mM EDTA stopped reactions, and reaction mixture (30 μ L) transferred to through the flicker that streptavidin applies get close in the microtiter plate (dodging plate (FlashPlates)), and cultivate whole night down at 4 ℃.Measure radioactive incorporating into by scintillation counting.

The composite example

Below for containing the representative pharmaceutical formulation of formula (I) compound.

Composite example 1

Tablet formulations

The following composition of meticulous mixing also is pressed into single indentation tablet with it.

Composite example 2

The capsule composite

The following composition of meticulous mixing and with in its duricrust gelatine capsule of packing into.

Composite example 3

Suspension formulations

Mix following composition to be formed for the suspension of oral administration.

Composite example 4

The injectable composite

Mix following composition to form the injectable composite.

Composite example 5

The suppository composite

By mixing compound of the present invention and Wei Tepusuo

H-15 (the triglyceride level of saturated vegetable fatty acid; Rick Heinrichs-Acnielsen Ltd. (Riches-Nelson, Inc.), New York (New York)) prepare the suppository that gross weight is 2.5g, and it has following composition:

Claims

1. formula (I) compound or its pharmaceutically acceptable salt or tautomer:

Wherein:

Or

Wherein HET is randomly through (X) _tReplace, X is selected from by alkyl, is substituted alkyl, alkoxyl group, is substituted alkoxyl group, amino, be substituted the group that amino, halogen, hydroxyl and nitro are formed; T equals 0,1 or 2 integer; W ¹, W ⁴And W ⁵Be N or CH independently; W ³Be N, CH or key, condition is to be no more than a nitrogen in the described dicyclo randomly to form the N-oxide compound through oxidation; And each dotted line is represented two singly-bound or two keys between the adjacent atom independently, and condition is when one in the dotted line is singly-bound, and described adjacent atom is respectively hung oneself 1 or 2 hydrogen atom replacement to satisfy its valence state;

Among D or the E one is C-R ^aAnd another person among D or the E is S;

Z is selected from the group that is made up of following:

(a) carboxyl and carboxyl ester;

(b)-C (X ⁴) NR ⁸R ⁹, X wherein ⁴For=O ,=NH or=the N-alkyl, R ⁸And R ⁹Be independently selected from by hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted the group that heterocyclic radical is formed, perhaps R ⁸And R ⁹Nitrogen-atoms together with its side joint forms heterocycle, is substituted heterocycle, heteroaryl ring or be substituted the heteroaryl ring group;

(c)-C (X ³) NR ²¹S (O) ₂R ⁴, X wherein ³Be selected from=O ,=NR ²⁴With=S, wherein R ²⁴For hydrogen, alkyl or be substituted alkyl; R ⁴Be selected from alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical, be substituted heterocyclic radical and NR ²²R ²³, R wherein ²¹, R ²²And R ²³Be hydrogen, alkyl independently, be substituted alkyl, cycloalkyl or be substituted cycloalkyl; Perhaps R ²¹With R ²²Or R ²²With R ²³Be joined together to form the heterocyclic radical that replaces through optional together with its bonded atom;

(d)-C (X ²)-N (R ³) CR ²R ^{2 '}C (=O) R ¹, X wherein ²Be selected from=O ,=S and=NR ¹¹, R wherein ¹¹Be hydrogen or alkyl; R ¹Select white-OR ⁷With-NR ⁸R ⁹, R wherein ⁷Select white hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocyclic radical and be substituted heterocyclic radical; R ⁸And R ⁹As hereinbefore defined;

2. compound according to claim 1, wherein Y is selected from the group that is made up of following: be substituted xenyl; Be substituted phenyl; Randomly condense with phenyl ring and have 1,2 or 3 be independently selected from the group that is made up of N, O or S heteroatomic and be substituted 6 yuan of heteroaryl rings, wherein said heteroatoms N or S are randomly through oxidation; Randomly condense with phenyl ring and have 1,2 or 3 heteroatomic 5 yuan of heteroaryl ring that are substituted that are independently selected from the group that is made up of N, O or S, wherein said heteroatoms N or S are randomly through oxidation.

3. compound according to claim 2; wherein Y is selected from the group that is made up of following: 4 '-chloro-4-methoxyl biphenyl-2-base; biphenyl-2-base; biphenyl-4-base; 4-amino-4 '-chlordiphenyl-2-base; 4 '-amino methyl-4-methoxyl biphenyl-2-base; 4-carbamyl-4 '-methoxyl biphenyl-2-base; 4-carbamyl-4 '-fluorine biphenyl-2-base; 4-carbamyl-4 '-methoxyl biphenyl-2-base; 4-carbamyl-4 '-nitrobiphenyl-2-base; 4-(carbamyl methyl-carbamyl) biphenyl-2-base; 4-(carbamyl methyl carbamyl)-4 '-chlordiphenyl-2-base; 4-carboxyl-4 '-chlordiphenyl-2-base; 3-carboxyl-4 '-methoxyl biphenyl-2-base; 4-carboxyl-4 '-methoxyl biphenyl-2-base; 4 '-carboxyl-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4-carboxyl methoxyl biphenyl-2-base; 4-carboxyl methoxyl group-4 '-chlordiphenyl-2-base; 4 '-chlordiphenyl-2-base; 4 '-chloro-4-chlordiphenyl-2-base; 4 '-chloro-4-(dimethyl aminoethyl carbamyl biphenyl-2-base; 4 '-chloro-4-(2-ethoxy ethoxy) biphenyl-2-base; 3 '-chloro-4 '-fluoro-4-methoxyl biphenyl-2-base; 4 '-chloro-4-fluorine biphenyl-2-base; 4 '-chloro-4-xenol-2-base; 3 '-chloro-4-methoxyl biphenyl-2-base; 4 '-chloro-4-methyl carbamyl biphenyl-2-base; 4 '-chloro-4-(2-methoxy ethoxy) biphenyl-2-base; 4 '-chloro-4-nitrobiphenyl-2-base; 4 '-chloro-4-(2-oxo-2-tetramethyleneimine-1-base oxethyl) biphenyl-2-base; 4 '-chloro-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4 '-chloro-4-(3-tetramethyleneimine-1-base propoxy-) biphenyl-2-base; 4 '-cyano group-4-methoxyl biphenyl-2-base; 3 '; 4 '-two chloro-4-methoxyl biphenyl-2-bases; 4; 4 '-dimethoxy-biphenyl-2-base; 3 ', 4 '-dimethoxy-4 '-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4 '-dimethylamino-4-methoxyl biphenyl-2-base; 4-(2-dimethyl aminoethyl carbamyl) biphenyl-2-base; 4 '-oxyethyl group-4-methoxyl biphenyl-2-base; 4 '-fluoro-4-methoxyl biphenyl-2-base; 4-xenol-2-base; 4-methoxyl biphenyl-2-base; 4-methoxyl group-4 '-xenol-2-base; 4-(2-methoxy ethoxy) biphenyl-2-base; 4-methoxyl group-4 '-methyl diphenyl-2-base; 4-methoxyl group-3 '-nitrobiphenyl-2-base; 4-methoxyl group-4 '-nitrobiphenyl-2-base; 4-methyl carbamyl biphenyl-2-base; 3 '-methyl-4-methoxyl biphenyl-2-base; 4 '-nitro-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4-(2-oxo-2-tetramethyleneimine-1-base oxethyl) biphenyl-2-base; 4-(3-tetramethyleneimine-1-base propoxy-) biphenyl-2-base and 4 '-trifluoromethyl-4-methoxyl biphenyl-2-base.

4. compound according to claim 2, the wherein said phenyl that is substituted is selected from by the substituting group of the following group that forms through one to three and replaces: halogen, heteroaryl, hydroxyl, nitro, cyano group, alkyl, be substituted alkyl, thiazolinyl, alkoxyl group, be substituted alkoxyl group, acyl group, amido, aminoacyl, amino, be substituted amino, carboxyl and carboxyl ester.

5. compound according to claim 2, wherein Y is selected from the group that is made up of following: be substituted quinolyl (qunolyl), be substituted benzofuryl, be substituted thiazolyl, be substituted furyl, be substituted thienyl, be substituted pyridyl, be substituted pyrazinyl, be substituted oxazolyl, be substituted isoxazolyl, be substituted pyrryl, be substituted imidazolyl, be substituted pyrrolidyl, be substituted pyrazolyl, be substituted isothiazolyl, be substituted 1,2,3-oxadiazoles base, be substituted 1,2, the 3-triazolyl, be substituted 1,3, the 4-thiadiazolyl group, be substituted pyrimidyl, be substituted 1,3, the 5-triazinyl, be substituted the indolizine base, the substituted indoles base, be substituted pseudoindoyl, be substituted indazolyl, be substituted benzothienyl, be substituted benzothiazolyl, be substituted purine radicals, be substituted quinolizinyl, be substituted quinolyl (qunolinyl), the substituted isoquinoline base, be substituted the cinnolines base, be substituted phthalazinyl, be substituted quinazolyl, be substituted quinoxalinyl, be substituted 1,8-naphthyridinyl and be substituted pteridyl.

6. compound according to claim 5, wherein Y is independently selected from by the substituting group of the following group that forms through one to three and replaces: alkyl, haloalkyl, halogen, hydroxyl, nitro, cyano group, alkoxyl group, be substituted alkoxyl group, acyl group, amido, aminoacyl, amino, be substituted amino, carboxyl and carboxyl ester.

7. compound according to claim 6, wherein Y is 2,4-dimethylthiazole-5-base.

8. compound according to claim 1, wherein Q is cycloalkyl or cycloalkenyl group.

9. compound according to claim 8, wherein Q is cyclohexyl or cyclohexenyl.

10. compound according to claim 1, wherein Z be carboxyl, carboxyl ester, carboxylic acid isostere ,-C (O) NR ⁸R ⁹Or-C (O) NHS (O) ₂R ⁴, R wherein ⁸And R ⁹As defined in claim 1 and R ⁴Be alkyl or aryl.

11. compound according to claim 10; wherein Z is carboxyl, carboxylate methyl ester, carboxylic acid, ethyl ester, 6-(β-D-glucuronic acid) ester, 1H-tetrazolium-5-base, 5-oxo-4; 5-dihydro-1; 2,4-oxadiazoles-3-base, N-2-cyano group-buserelin, N-2-(1H-tetrazolium-5-yl) buserelin, methyl sulphonyl aminocarboxyl, trifluoromethyl sulfonyl aminocarboxyl or phenyl sulfonyl amino carbonyl.

12. compound according to claim 11, wherein Z is a carboxyl.

13. compound according to claim 1, wherein D is that CH and E are S.

14. compound according to claim 1, wherein R is for being substituted alkyl, and the wherein said alkyl that is substituted is selected from the group that is made up of following: aminoalkyl group, be substituted aminoalkyl group, arylalkyl, be substituted arylalkyl, heteroarylalkyl, be substituted heteroarylalkyl, heterocyclic radical alkyl, be substituted the heterocyclic radical alkyl ,-CH ₂COOH and-CH ₂CONR ¹²R ¹³, R wherein ¹²And R ¹³Be independently selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, alkoxyl group, be substituted alkoxyl group ,-(CH ₂) _0-3R ¹⁶With-NR ¹⁷R ¹⁸, or R ¹²And R ¹³Form the heterocycle that is substituted or is unsubstituted with the nitrogen-atoms that it connected, condition is R ¹²With R ¹³Be not all hydrogen; R wherein ¹⁶Be aryl, heteroaryl or heterocyclic radical; And R ¹⁷And R ¹⁸Be hydrogen or alkyl independently, or R ¹⁷And R ¹⁸Be joined together to form heterocycle with 4 to 7 annular atomses together with the nitrogen-atoms that it connected.

15. compound according to claim 1, wherein R is-CH ₂CONR ¹²R ¹³, and R ¹²Or R ¹³In at least one be alkyl, be substituted alkyl or heteroaryl.

16. compound according to claim 15, wherein R ¹²Or R ¹³In at least one be methyl, carboxymethyl, 2-hydroxyethyl, 2-morpholine-4-base ethyl or tetrazolium-5-base.

17. compound according to claim 14, wherein R is-CH ₂CONR ¹²R ¹³, and R ¹²And R ¹³Form the heterocycle that is substituted or is unsubstituted with the nitrogen-atoms that it connected.

18. compound according to claim 17, wherein R ¹²And R ¹³The tetramethyleneimine basic ring that forms the morpholinyl that is substituted or is unsubstituted, the piperidyl that is substituted or is unsubstituted or be substituted or be unsubstituted with the nitrogen-atoms that it connected.

19. compound according to claim 18, the wherein said morpholinyl that is substituted or is unsubstituted, piperidyl or tetramethyleneimine basic ring are selected from the group that is made up of following: morpholinyl, 4-tetramethyleneimine-1-base-piperidyl, piperidyl, 4-hydroxy piperidine base, 4-carboxyl piperidyl, 4-dimethylamino piperidyl, 4-diethylamino piperidyl, 2-methylpyrrole alkyl, 4-morpholine-4-base-piperidyl, 3,5-dimethyl-morpholine-4-base, 4-methyl piperidine base.

20. compound according to claim 14; wherein R is selected from N; N-dimethylamino-carbonyl methyl; [N-(4-hydroxyl-1; 1-dioxo tetrahydrochysene-3-thienyl) amino]-the carbonyl methyl; (cyclopropyl methylamino)-carbonyl methyl; (third-2-alkynes-1-base is amino)-carbonyl methyl; (2-(morpholinyl) second-1-base is amino)-carbonyl methyl; (phenyl sulfonyl amino)-carbonyl methyl; [N-benzylamino]-carbonyl methyl; (N-(4-methyl sulphonyl-benzyl) amino)-carbonyl methyl; (tryptophyl)-carbonyl methyl; (tyrosine)-carbonyl methyl; (N-(1-carboxyl third-1-base is amino)-carbonyl methyl; (N-(2-carboxyl second-1-yl)-amino)-carbonyl methyl; (N-(4-carboxyl benzyl)-amino)-carbonyl methyl; N-[3-(N '-(4-(vinylformic acid)-phenyl) formamido-) tetramethyleneimine-3-yl] amino-carbonyl methyl; N-[4-(N '-(4-(vinylformic acid)-phenyl) formamido-) piperidin-4-yl] amino-carbonyl methyl; [2-(N; the N-dimethylamino) second-1-base is amino]-the carbonyl methyl; [(1-(5-methyl-4H-1; 2; 4-triazole-3-yl) amino ethyl)]-the carbonyl methyl; (1-methyl isophthalic acid-[N-(1-methyl-2-carboxyl-1H-indoles-5-yl) aminocarboxyl] second-1-base amino-carbonyl methyl; [N-(1-methylpyrrolidin-3-base-ethyl)-amino]-carbonyl methyl; (1-methyl isophthalic acid-[N-(4-(vinylformic acid) phenyl) aminocarboxyl] second-1-base amino-carbonyl methyl; (1-methyl isophthalic acid-[N-(4-(2-carboxyl-furans-5-yl) phenyl) aminocarboxyl] second-1-base amino-carbonyl methyl; (1-methyl isophthalic acid-[N-(4-(4-carboxyl-thiazol-2-yl) phenyl) aminocarboxyl] second-1-base amino-carbonyl methyl; (2-(4-methylpiperazine-1-yl) second-1-base is amino)-carbonyl methyl; [(1-methylpyrrolidin-3-yl) methylamino]-carbonyl methyl; [N-(1-methyl piperidine-3-base-methyl)-amino]-carbonyl methyl; (1-piperidines-1-basic ring amyl group) methylamino]-the carbonyl methyl; (1-(ethanoyl)-tetramethyleneimine-2-ylmethyl) amino)-the carbonyl methyl; [(2-(N; the N-dimethylamino)-and carbonyl) methylamino]-the carbonyl methyl; [N-(1; 1-dioxo tetrahydrochysene-3-thienyl) methylamino]-the carbonyl methyl; (N-methyl-N-cyclohexyl-amino)-carbonyl methyl; (N-methyl-N-carboxymethyl-amino)-carbonyl methyl; [N-methyl-N-benzyl-amino]-carbonyl methyl; (N-methyl-N-(N '; N '-dimethylamino ethanoyl)-amino)-the carbonyl methyl; [N-methyl-N-phenyl-amino]-carbonyl methyl; (N-methyl-N-isopropyl propyl group-amino)-carbonyl methyl; (N-methyl-N-(N '-methyl piperidine-4-yl) amino)-the carbonyl methyl; [N-methyl-N-(1-methyl piperidine-4-yl) amino]-carbonyl methyl; [N-methyl-N-(1-methyl piperidine-4-base-methyl)-amino]-carbonyl methyl; [N-methyl-N-(1-methyl piperidine-3-base-methyl)-amino]-carbonyl methyl; [N-methyl-N-(1-methylpyrazine-2-base-methyl)-amino]-carbonyl methyl; [N-methyl-N-(5-methyl isophthalic acid H-imidazoles-2-ylmethyl)-amino]-carbonyl methyl; (N-methyl-N-[2-(hydroxyl) second-1-yl] amino)-the carbonyl methyl; (N-methyl-N-[2-(N '; N '-dimethylamino) second-1-yl] amino)-the carbonyl methyl; N-methyl-N-[2-(N '; N '-diethylamino) second-1-yl] amino)-the carbonyl methyl; (N-methyl-N-[2-(pyridine-2-yl) second-1-yl] amino)-the carbonyl methyl; (N-methyl-N-[2-(pyridin-4-yl) second-1-yl] amino)-the carbonyl methyl; [(1-(1 for N-methyl-N-; the 3-thiazol-2-yl) ethyl)-amino]-the carbonyl methyl; (N-methyl-N-[3-(N '; N '-dimethylamino) third-1-yl] amino)-the carbonyl methyl; (N-methyl-N-(1-carboxyl-2-methyl-prop-1-yl)-amino)-carbonyl methyl; (N-ethyl-N-propyl group-amino)-carbonyl methyl; (N-ethyl-N-[2-(methoxyl group) second-1-yl] amino)-the carbonyl methyl; (N-ethyl-N-[2-(N '; N '-diethylamino) second-1-yl] amino)-the carbonyl methyl; [7-methyl-2; 7-diaza spiro [44] ninth of the ten Heavenly Stems-2-yl]-the carbonyl methyl; (5-methyl-2; 5-diazabicyclo [2.2.1] heptan-2-yl)-the carbonyl methyl; (4-methyl isophthalic acid; 4-Diazesuberane-1-yl)-the carbonyl methyl; (piperidyl)-carbonyl methyl; (4-carboxyl-piperidyl)-carbonyl methyl; (3-carboxyl piperidyl)-carbonyl methyl; (4-hydroxy piperidine base)-carbonyl methyl; (4-(2-hydroxyl second-1-yl) piperidines-1-yl)-carbonyl methyl; [4-(N; the N-dimethylamino)-piperidines-1-yl]-the carbonyl methyl; (3-(N; the N-dimethylamino)-methyl piperidine-1-yl)-the carbonyl methyl; (2-(2-(N; the N-dimethylamino)-and second-1-yl) piperidines-1-yl)-the carbonyl methyl; [4-(4-methyl-4H-1; 2; 4-triazole-3-yl) piperidines-1-yl]-the carbonyl methyl; (4-pyrrolidyl-piperidyl)-carbonyl methyl; (3-pyrrolidyl-piperidyl)-carbonyl methyl; [4-(N; the N-diethylamino)-piperidines-1-yl]-the carbonyl methyl; (4-(azetidine-1-yl)-piperidines-1-yl)-carbonyl methyl; (4-(piperidines-1-yl)-piperidines-1-yl)-carbonyl methyl; (hexahydropyrrolo also [1; 2-a] pyrazine-2 (1H)-yl)-carbonyl methyl; [(2-(N; the N-dimethylamino)-and methyl) morpholinyl]-the carbonyl methyl; (3; the 5-dimethylated morpholinyl)-the carbonyl methyl; (thio-morpholinyl)-carbonyl methyl; morpholinyl-carbonyl methyl; (pyrrolidyl)-carbonyl methyl; (2-carboxyl-tetramethyleneimine-1-yl)-carbonyl methyl; (2-(carboxyl)-4-hydroxyl-tetramethyleneimine-1-yl)-carbonyl methyl; (2-methane amide-tetramethyleneimine-1-yl)-carbonyl methyl; (2-(N; N-dimethylamino carbonyl)-tetramethyleneimine-1-yl)-the carbonyl methyl; (3-(N '; N '-dimethylamino)-tetramethyleneimine-1-yl)-the carbonyl methyl; (3-(N '; N '-diethylamino)-tetramethyleneimine-1-yl)-the carbonyl methyl; (3-(pyridin-3-yl)-tetramethyleneimine-1-yl)-carbonyl methyl; (2-pyridin-4-yl tetramethyleneimine-1-yl)-carbonyl methyl; piperazine-1-base-carbonyl methyl; (4-methylpiperazine base)-carbonyl methyl; (4-(carboxymethyl)-piperazine-1-yl)-carbonyl methyl; (4-(2-hydroxyl second-1-yl) piperazine-1-yl)-carbonyl methyl; (4-(sec.-propyl) piperazine-1-yl)-carbonyl methyl; (4-(2-methoxyl group second-1-yl) piperazine-1-yl)-carbonyl methyl; (4-(ethyl) piperazine-1-yl)-carbonyl methyl; (4-(N ', N '-dimethylamino ethanoyl)-piperazine-1-yl)-carbonyl methyl and (4-(6-methoxypyridine-2-yl) piperazine-1-yl)-carbonyl methyl.

21. compound according to claim 1, wherein t is 0.

22. compound according to claim 1, wherein t be 1 and X be amino, nitro, methyl or halogen.

23. according to the described compound of arbitrary claim in the claim 1 to 22, wherein HET is for randomly through (X) _t1 of replacement, the 4-phenylene, wherein X and t are as defined in claim 1.

24. compound according to claim 23, wherein t is 0.

25. according to the described compound of arbitrary claim in the claim 1 to 22, wherein HET is for randomly through (X) _tReplace

Wherein X, t, W ¹, W ³, W ⁴And W ⁵As defined in claim 1.

26. compound according to claim 25, wherein W ¹Be nitrogen.

27. compound according to claim 26, wherein HET is selected from the group that is made up of following:

With

Wherein X and t are as defined in claim 1.

28. compound or its a pharmaceutically acceptable salt or tautomer with formula (Ia):

Wherein:

T equals 0,1 or 2 integer;

Q is selected from the group that is made up of cyclohexyl and cyclopentyl;

R ¹²And R ¹³3 be independently selected from hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, alkoxyl group, be substituted alkoxyl group ,-(CH ₂) _0-3R ¹⁶With-NR ¹⁷R ¹⁸Or R ¹²And R ¹³Form the heterocycle that is substituted or is unsubstituted with the nitrogen-atoms that it connected, condition is R ¹²With R ¹³Be not all hydrogen; R wherein ¹⁶Be aryl, heteroaryl or heterocyclic radical; And R ¹⁷And R ¹⁸Be hydrogen or alkyl independently, or R ¹⁷And R ¹⁸Be connected to form heterocycle with 4 to 7 annular atomses together with the nitrogen-atoms that it connected;

Among A or the B one is C-R ^aAnd another person among A or the B is S;

R ^aSelect Bai Youqing, alkyl and be substituted the group that alkyl is formed; And

29. compound according to claim 28, wherein Y is selected from the group that is made up of following: be substituted xenyl; Be substituted phenyl; Randomly condense with phenyl ring and have 1,2 or 3 be independently selected from the group that is made up of N, O or S heteroatomic and be substituted 6 yuan of heteroaryl rings, wherein said heteroatoms N or S are randomly through oxidation; Randomly condense with phenyl ring and have 1,2 or 3 be independently selected from the group that is made up of N, O or S heteroatomic and be substituted 5 yuan of heteroaryl rings, wherein said heteroatoms N or S are randomly through oxidation.

30. compound according to claim 29; wherein Y is selected from the group that is made up of following: 4 '-chloro-4-methoxyl biphenyl-2-base; biphenyl-2-base; biphenyl-4-base; 4-amino-4 '-chlordiphenyl-2-base; 4 '-amino methyl-4-methoxyl biphenyl-2-base; 4-carbamyl-4 '-methoxyl biphenyl-2-base; 4-carbamyl-4 '-fluorine biphenyl-2-base; 4-carbamyl-4 '-methoxyl biphenyl-2-base; 4-carbamyl-4 '-nitrobiphenyl-2-base; 4-(carbamyl methyl-carbamyl) biphenyl-2-base; 4-(carbamyl methyl carbamyl)-4 '-chlordiphenyl-2-base; 4-carboxyl-4 '-chlordiphenyl-2-base; 3-carboxyl-4 '-methoxyl biphenyl-2-base; 4-carboxyl-4 '-methoxyl biphenyl-2-base; 4 '-carboxyl-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4-carboxyl methoxyl biphenyl-2-base; 4-carboxyl methoxyl group-4 '-chlordiphenyl-2-base; 4 '-chlordiphenyl-2-base; 4 '-chloro-4-chlordiphenyl-2-base; 4 '-chloro-4-(dimethyl aminoethyl carbamyl biphenyl-2-base; 4 '-chloro-4-(2-ethoxy ethoxy) biphenyl-2-base; 3 '-chloro-4 '-fluoro-4-methoxyl biphenyl-2-base; 4 '-chloro-4-fluorine biphenyl-2-base; 4 '-chloro-4-xenol-2-base; 3 '-chloro-4-methoxyl biphenyl-2-base; 4 '-chloro-4-methyl carbamyl biphenyl-2-base; 4 '-chloro-4-(2-methoxy ethoxy) biphenyl-2-base; 4 '-chloro-4-nitrobiphenyl-2-base; 4 '-chloro-4-(2-oxo-2-tetramethyleneimine-1-base oxethyl) biphenyl-2-base; 4 '-chloro-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4 '-chloro-4-(3-tetramethyleneimine-1-base propoxy-) biphenyl-2-base; 4 '-cyano group-4-methoxyl biphenyl-2-base; 3 '; 4 '-two chloro-4-methoxyl biphenyl-2-bases; 4; 4 '-dimethoxy-biphenyl-2-base; 3 ', 4 '-dimethoxy-4 '-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4 '-dimethylamino-4-methoxyl biphenyl-2-base; 4-(2-dimethyl aminoethyl carbamyl) biphenyl-2-base; 4 '-oxyethyl group-4-methoxyl biphenyl-2-base; 4 '-fluoro-4-methoxyl biphenyl-2-base; 4-xenol-2-base; 4-methoxyl biphenyl-2-base; 4-methoxyl group-4 '-xenol-2-base; 4-(2-methoxy ethoxy) biphenyl-2-base; 4-methoxyl group-4 '-methyl diphenyl-2-base; 4-methoxyl group-3 '-nitrobiphenyl-2-base; 4-methoxyl group-4 '-nitrobiphenyl-2-base; 4-methyl carbamyl biphenyl-2-base; 3 '-methyl-4-methoxyl biphenyl-2-base; 4 '-nitro-4-(tetramethyleneimine-1-base carbonyl) biphenyl-2-base; 4-(2-oxo-2-tetramethyleneimine-1-base oxethyl) biphenyl-2-base; 4-(3-tetramethyleneimine-1-base propoxy-) biphenyl-2-base and 4 '-trifluoromethyl-4-methoxyl biphenyl-2-base.

31. compound according to claim 29, the wherein said phenyl that is substituted is selected from by the substituting group of the following group that forms through one to three and replaces: halogen, heteroaryl, hydroxyl, nitro, cyano group, alkyl, be substituted alkyl, thiazolinyl, alkoxyl group, be substituted alkoxyl group, acyl group, amido, aminoacyl, amino, be substituted amino, carboxyl and carboxyl ester.

32. compound according to claim 29, wherein Y is selected from the group that is made up of following: be substituted quinolyl (quinolyl), be substituted benzofuryl, be substituted thiazolyl, be substituted furyl, be substituted thienyl, be substituted pyridyl, be substituted pyrazinyl, be substituted oxazolyl, be substituted isoxazolyl, be substituted pyrryl, be substituted imidazolyl, be substituted pyrrolidyl, be substituted pyrazolyl, be substituted isothiazolyl, be substituted 1,2,3-oxadiazoles base, be substituted 1,2, the 3-triazolyl, be substituted 1,3, the 4-thiadiazolyl group, be substituted pyrimidyl, be substituted 1,3, the 5-triazinyl, be substituted the indolizine base, the substituted indoles base, be substituted pseudoindoyl, be substituted indazolyl, be substituted benzothienyl, be substituted benzothiazolyl, be substituted purine radicals, be substituted quinolizinyl, be substituted quinolyl (quinolinyl), the substituted isoquinoline base, be substituted the cinnolines base, be substituted phthalazinyl, be substituted quinazolyl, be substituted quinoxalinyl, be substituted 1,8-naphthyridinyl and be substituted pteridyl.

33. compound according to claim 32, wherein Y is independently selected from by the substituting group of the following group that forms through one to three and replaces: alkyl, haloalkyl, halogen, hydroxyl, nitro, cyano group, alkoxyl group, be substituted alkoxyl group, acyl group, amido, aminoacyl, amino, be substituted amino, carboxyl and carboxyl ester.

34. compound according to claim 33, wherein Y is 2,4-dimethylthiazole-5-base.

35. compound according to claim 28, wherein Q is cyclohexyl or cyclohexenyl.

36. compound according to claim 35; wherein Z is carboxylate methyl ester, carboxylic acid, ethyl ester, 6-(β-D-glucuronic acid) ester, 1H-tetrazolium-5-base, 5-oxo-4; 5-dihydro-1; 2,4-oxadiazoles-3-base, N-2-cyano group-buserelin, N-2-(1H-tetrazolium-5-yl) buserelin, methyl sulphonyl aminocarboxyl, trifluoromethyl sulfonyl aminocarboxyl or phenyl sulfonyl amino carbonyl.

37. compound according to claim 36, wherein Z is a carboxyl.

38. compound according to claim 28, wherein R ¹²Or R ¹³In at least one be alkyl, be substituted alkyl or heteroaryl.

39. according to the described compound of claim 38, wherein R ¹²Or R ¹³In at least one be methyl, carboxymethyl, 2-hydroxyethyl, 2-morpholine-4-base ethyl or tetrazolium-5-base.

40. compound according to claim 28, wherein R ¹²And R ¹³Form the heterocycle that is substituted or is unsubstituted with the nitrogen-atoms that it connected.

41. according to the described compound of claim 40, wherein R ¹²And R ¹³The tetramethyleneimine basic ring that forms the morpholinyl that is substituted or is unsubstituted, the piperidyl that is substituted or is unsubstituted or be substituted or be unsubstituted with the nitrogen-atoms that it connected.

42. according to the described compound of claim 41, the wherein said morpholinyl that is substituted or is unsubstituted, piperidyl or tetramethyleneimine basic ring are selected from the group that is made up of following: morpholinyl, 4-tetramethyleneimine-1-base-piperidyl, piperidyl, 4-hydroxy piperidine base, 4-carboxyl piperidyl, 4-dimethylamino piperidyl, 4-diethylamino piperidyl, 2-methylpyrrole alkyl, 4-morpholine-4-base-piperidyl, 3,5-dimethyl-morpholine-4-base, 4-methyl piperidine base.

43. compound according to claim 28, wherein R ¹²And R ¹³Form with the nitrogen-atoms that it connected and to be selected from following group: N; the N-dimethylamino; N-(4-hydroxyl-1; 1-dioxo tetrahydrochysene-3-thienyl) amino; the cyclopropyl methylamino; third-2-alkynes-1-base is amino; 2-(morpholinyl) second-1-base is amino; phenyl sulfonyl amino; the N-benzylamino; N-(4-methyl sulphonyl-benzyl) amino; tryptophyl; tyrosine; N-1-carboxyl third-1-base is amino; N-(2-carboxyl second-1-yl)-amino; N-(4-carboxyl benzyl)-amino; N-[3-(N '-(4-(vinylformic acid)-phenyl) formamido-) tetramethyleneimine-3-yl] amino; N-[4-(N '-(4-(vinylformic acid)-phenyl) formamido-) piperidin-4-yl] amino; 2-(N; the N-dimethylamino) second-1-base is amino; (1-(5-methyl-4H-1; 2; 4-triazole-3-yl) amino ethyl); 1-methyl isophthalic acid-[N-(1-methyl-2-carboxyl-1H-indoles-5-yl) aminocarboxyl] second-1-base is amino; N-(1-methylpyrrolidin-3-base-ethyl)-amino; 1-methyl isophthalic acid-[N-(4-(vinylformic acid) phenyl) aminocarboxyl] second-1-base is amino; 1-methyl isophthalic acid-[N-(4-(2-carboxyl-furans-5-yl) phenyl) aminocarboxyl] second-1-base is amino; 1-methyl isophthalic acid-[N-(4-(4-carboxyl-thiazol-2-yl) phenyl) aminocarboxyl] second-1-base is amino; 2-(4-methylpiperazine-1-yl) second-1-base is amino; (1-methylpyrrolidin-3-yl) methylamino; N-(1-methyl piperidine-3-base-methyl)-amino; (1-piperidines-1-basic ring amyl group) methylamino; 1-(ethanoyl)-tetramethyleneimine-2-ylmethyl) amino; (2-(N; the N-dimethylamino)-and carbonyl) methylamino; N-(1; 1-dioxo tetrahydrochysene-3-thienyl) methylamino; N-methyl-N-cyclohexyl-amino; N-methyl-N-carboxymethyl-amino; N-methyl-N-benzyl-amino; N-methyl-N-(N '; N '-dimethylamino ethanoyl)-amino; N-methyl-N-phenyl-amino; N-methyl-N-isopropyl propyl group-amino; N-methyl-N-(N '-methyl piperidine-4-yl) amino; N-methyl-N-(1-methyl piperidine-4-yl) amino; N-methyl-N-(1-methyl piperidine-4-base-methyl)-amino; N-methyl-N-(1-methyl piperidine-3-base-methyl)-amino; N-methyl-N-(1-methylpyrazine-2-base-methyl)-amino; N-methyl-N-(5-methyl isophthalic acid H-imidazoles-2-ylmethyl)-amino; N-methyl-N-[2-(hydroxyl) second-1-yl] amino; N-methyl-N-[2-(N '; N '-dimethylamino) second-1-yl] amino; N-methyl-N-[2-(N '; N '-diethylamino) second-1-yl] amino; N-methyl-N-[2-(pyridine-2-yl) second-1-yl] amino; N-methyl-N-[2-(pyridin-4-yl) second-1-yl] amino; (1-(1 for N-methyl-N-; the 3-thiazol-2-yl) ethyl)-amino; N-methyl-N-[3-(N '; N '-dimethylamino) third-1-yl] amino; N-methyl-N-(1-carboxyl-2-methyl-prop-1-yl)-amino; N-ethyl-N-propyl group-amino; N-ethyl-N-[2-(methoxyl group) second-1-yl] amino; N-ethyl-N-[2-(N '; N '-diethylamino) second-1-yl] amino; 7-methyl-2; 7-diaza spiro [4.4] ninth of the ten Heavenly Stems-2-base; 5-methyl-2; 5-diazabicyclo [2.2.1] heptan-2-base; the 4-methyl isophthalic acid; 4-Diazesuberane-1-base; piperidyl; 4-carboxyl-piperidyl; 3-carboxyl piperidyl; 4-hydroxy piperidine base; 4-(2-hydroxyl second-1-yl) piperidines-1-base; 4-(N; the N-dimethylamino)-piperidines-1-base; 3-(N; the N-dimethylamino)-methyl piperidine-1-base; 2-(2-(N; the N-dimethylamino)-and second-1-yl) piperidines-1-base; 4-(4-methyl-4H-1; 2; 4-triazole-3-yl) piperidines-1-base; 4-pyrrolidyl-piperidyl; 3-pyrrolidyl-piperidyl; 4-(N; the N-diethylamino)-piperidines-1-base; 4-(azetidine-1-yl)-piperidines-1-base; 4-(piperidines-1-yl)-piperidines-1-base; hexahydropyrrolo also [1; 2-a] pyrazine-2 (1H)-Ji; (2-(N; the N-dimethylamino)-and methyl) morpholinyl; 3; the 5-dimethylated morpholinyl; thio-morpholinyl; morpholinyl; pyrrolidyl; 2-carboxyl-tetramethyleneimine-1-base; 2-(carboxyl)-4-hydroxyl-tetramethyleneimine-1-base; 2-methane amide-tetramethyleneimine-1-base; 2-(N; N-dimethylamino carbonyl)-tetramethyleneimine-1-base; 3-(N '; N '-dimethylamino)-tetramethyleneimine-1-base; 3-(N '; N '-diethylamino)-tetramethyleneimine-1-base; 3-(pyridin-3-yl)-tetramethyleneimine-1-base; 2-pyridin-4-yl tetramethyleneimine-1-base; piperazine-1-base; 4-methylpiperazine base; 4-(carboxymethyl)-piperazine-1-base; 4-(2-hydroxyl second-1-yl) piperazine-1-base; 4-(sec.-propyl) piperazine-1-base; 4-(2-methoxyl group second-1-yl) piperazine-1-base; 4-(ethyl) piperazine-1-base; 4-(N ', N ' dimethylamino ethanoyl)-piperazine-1-base and 4-(6-methoxypyridine-2-yl) piperazine-1-base.

44. compound according to claim 28, wherein t is 0.

45. compound according to claim 28, wherein t be 1 and X be amino, nitro, methyl or halogen.

46. compound according to claim 28, wherein D is that CH and E are S.

47. a compound that is selected from table 1 or its tautomer, pharmaceutically acceptable salt or part salt.

48. a medical composition, its comprise pharmaceutically acceptable supporting agent and the treatment significant quantity according to the described compound of arbitrary claim in the claim 1,28 or 47.

49. the purposes according to the described compound of arbitrary claim in the claim 1,28 or 47, it is used for preparation for treating or prevent the mammiferous medicine for treating viral infections that is mediated by flaviviridae (Flaviviridae) virus to small part.

50. a treatment or prevent mammiferous to the method for small part by the virus infection that flaviviridae mediated, its comprise to described Mammals throw with according to the described composition of claim 48.

51. according to the described method of claim 50, wherein said virus infection is mediated by hepatitis C virus.

52., hepatitis C virus is had the combination of active medicament with one or more of treatment significant quantity according to the described method of claim 50.

53. according to the described method of claim 52, wherein said to hepatitis C virus have that active medicament is that HCV proteolytic enzyme, HCV polysaccharase, HCV helicase, HCV NS4B albumen, HCV enter, HCV assembles, HCV disengages, HCV NS5A egg from and inosine 5 '-inhibitor of single phosphate dehydrogenase.